Tetrahydropyran compounds as tachykinin antagonists

ABSTRACT

The present invention relates to the compounds of the formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9  and W are as defined herein, and pharmaceutically acceptable salts thereof; the compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migraine, emesis or postherpetic neuralgia.

This invention relates to a class of tetrahydropyran compounds which areuseful as tachykinin antagonists. More particularly, the compounds ofthe invention are useful as neurokinin 1 (NK-1) receptor antagonists.

The present invention provides compounds of the formula (I):

and pharmaceutically acceptable salts thereofwherein

W represents:

R¹ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, fluoroC₁₋₆alkyl,fluoroC₁₋₆alkoxy, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, NO₂, CN,SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₄alkyl substituted by C₁₋₄alkoxy, wherein R^(a) andR^(b) each independently represent hydrogen or C₁₋₄alkyl;

R² is hydrogen, halogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl or C₁₋₆alkoxysubstituted by C₁₋₄alkoxy;

R³ is hydrogen, halogen or fluoroC₁₋₆alkyl;

R⁴ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, fluoroC₁₋₆alkyl,fluoroC₁₋₆alkoxy, hydroxy, NO₂, CN, SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a),CONR^(a)R^(b), C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₄alkyl substituted byC₁₋₄alkoxy, wherein R^(a) and R^(b) are as previously defined;

R⁵ is hydrogen, halogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl or C₁₋₆alkoxysubstituted by C₁₋₄alkoxy;

R⁶ represents hydrogen or a C₁₋₄-alkyl group optionally substituted by ahydroxy group;

R⁷ represents hydrogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl, hydroxy, C₁₋₆alkoxyor hydroxyC₁₋₆alkyl;

R⁸ and R⁹ each independently represent hydrogen, halogen, C₁₋₆alkyl,CH₂OR^(c), oxo, CO₂R^(a) or CONR^(a)R^(b) where R^(a) and R^(b) are aspreviously defined and R^(c) represents hydrogen, C₁₋₆alkyl or phenyl;

and pharmaceutically acceptable salts thereof;

wherein when W is

A represents an oxygen atom or a CH₂ group;

B represents an oxygen atom or a CH₂ group, with the proviso that when Ais an oxygen atom, B is a CH₂ group, and when A is a CH₂ group, B is anoxygen atom;

n is 1 or 2;

m is 1, 2 or 3, with the proviso that the sum total of m+n is 2, 3 or 4;

R¹⁰ is hydrogen, halogen, hydroxy, C₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,C₂₋₆alkenyl or C₂₋₆alkynyl;

R¹¹ is hydrogen, halogen, hydroxy or C₁₋₄alkyl;

or R¹⁰ and R¹¹ may together represent an oxo (═O) group, with theproviso that the oxo group is not adjacent to the oxygen atomrepresented by either A or B;

wherein one or both of R¹⁰ and R¹¹ may replace one or both hydrogenatoms in the CH₂ group represented by A or B;

wherein when W is

R¹⁰ is hydrogen, C₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl,C₂₋₄alkyl substituted by a C₁₋₄alkoxy or hydroxyl group;

R¹¹ is hydrogen or C₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl,or C₁₋₄alkyl substituted by C₁₋₄alkoxy, hydroxyl or phenyl, wherein saidphenyl group is optionally substituted by one, two or three substituentsselected from C₄alkyl, C₁₋₆alkoxy, halogen and trifluoromethyl;

or R¹⁰, R¹¹ and the nitrogen atom to which they are attached form aheteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by oneor two groups selected from hydroxy, COR^(e), CO₂R^(e), C₁₋₄alkyloptionally substituted by a C₁₋₄alkoxy or hydroxyl group, or C₁₋₄alkoxyoptionally substituted by a C₁₋₄alkoxy or hydroxyl group, whichheteroaliphatic ring may optionally contain an oxygen or sulphur ringatom, a group S(O) or S(O)₂ or a second nitrogen atom which will be partof a NH or NR^(d) moiety, where R^(d) is C₁₋₄alkyl optionallysubstituted by hydroxy or C₁₋₄alkoxy, and where R^(e) is hydrogen,C₁₋₄alkyl or benzyl;

R¹² represents halogen, hydroxy, C₁₋₄alkoxy or fluoroC₁₋₄alkoxy, orwhere p is 2, then two R⁹ groups may together represent an oxo (═O)group;

m is zero, 1 or 2;

n is 1, 2 or 3, with the proviso that the sum total of m+n is 2 or 3;and

p is zero, 1 or 2;

wherein when W is

A represents NR¹² or S(O)_(q);

B represents NR¹² or S(O)_(q), with the proviso that when A is S(O)_(q),then B is NR¹², and when A is NR¹², then B is S(O)_(q);

R¹⁰ and R¹¹ each independently represent hydrogen, fluorine, COR^(e),CO₂R^(e), C₁₋₄alkyl optionally substituted by a C₁₋₄alkoxy or hydroxylgroup, or C₁₋₄alkoxy optionally substituted by a C₁₋₄alkoxy or hydroxylgroup, where Re is hydrogen, methyl ethyl or benzyl;

or, when they are attached to the same carbon atom, R¹⁰ and R¹¹ maytogether represent ═O, ═CHCO₂R^(a), —O(CH₂)_(m)O—, —CH₂O(CH₂)_(p)—,—CH₂OCH₂C(O)—, —CH₂OCH₂CH(OH)—, —CH₂OCH₂C(CH₃)₂—, —CH₂OC(CH₃)₂CH₂—,—C(CH₃)₂OCH₂CH₂—, —C₂C(O)OCH₂—, —OC(O)CH₂CH₂—, —C(O)OCH₂CH₂—,—C(O)OC(CH₃)₂CH₂—, —C(O)OCH₂C(CH₃)₂—, —OCH₂(CH₂)_(p)—, —OC(CH₃)₂CH₂CH₂—,—OCH₂C(CH₃)₂CH₂—, —OCH₂CH₂C(CH₃)₂—, —OCH₂CH═CHCH₂—, —OCH₂CH(OH)CH₂CH₂—,—OCH₂CH₂CH(OH)CH₂—, —OCH₂C(O)CH₂CH₂—, —OCH₂CH₂C(O)CH₂—, or a group ofthe formula

where R^(a) is as previously defined,

or, where they are attached to adjacent carbon atoms, R¹⁰ and R¹¹ maytogether represent —OCH₂CH₂— or —OCH₂CH(OH)—, or R¹⁰ and R¹¹ maytogether form a fused benzene ring;

or, R¹⁰ and R¹¹ together form a C₁₋₂alkylene bridge across thepyrrolidine, piperidine, morpholine or piperazine ring to which they areattached;

R¹² represents hydrogen, benzyl, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, COC₁₋₆alkyl, CO₂C₁₋₆alkyl or C₂alkylsubstituted by a C₁₋₄alkoxy or hydroxyl group;

R¹³ represents hydrogen, halogen, hydroxy, C₁₋₄alkyl, hydroxyC₁₋₄alkylor fluoroC₁₋₄alkyl;

m is 1 or 2;

p is 1, 2 or 3; and

q is zero, 1 or 2;

wherein when W is

R¹⁰ represents halogen, hydroxy, C₁₋₄alkoxy or fluoroC₁₋₄alkoxy, orwhere p is 2, then two R¹⁰ groups may together represent an oxo (═O)group;

R¹¹ represents hydrogen, benzyl, C₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, or C₂₋₄alkyl substituted by a C₁₋₄alkoxy orhydroxyl group;

m is zero, 1 or 2;

n is zero or 1, with the proviso that the sum total of m+n is 1, 2 or 3,and with the further proviso that when m is 2 then n is 1; and

p is zero, 1 or 2;

wherein when W is

X represents C—, —CF₂—, —CH(OH)— or —CH(OC₁₋₄alkyl)-;

Y represents —NR¹³R¹⁴ or a group selected from:

Z represents O, S, SO, SO₂ or NR¹²;

R¹⁰ represents hydrogen, halogen, hydroxy, C₁₋₄alkoxy orfluoroC₁₋₄alkoxy;

R¹¹ represents hydrogen, halogen, hydroxy, C₁₋₄alkoxy orfluoroC₁₋₄alkoxy;

or R¹⁰ and R¹¹ together represent an oxo (═O) group;

R¹² represents C₁₋₆alkyl, COC₁₋₆alkyl, CO₂C₁₋₆alkyl;

R¹³ and R¹⁴ each independently represent hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl or fluoroC₁₋₆alkyl, wherein said alkyl or cycloalkylgroups are optionally substituted with a group selected from hydroxy,C₁₋₄alkoxy, —NHCOC₁₋₄alkyl or —NHCO₂C₁₋₄alkyl;

m is 1 or 2;

n is 1 or 2; and

p is 1 or 2;

wherein when W is

X represents —CHR¹³—, CF₂— or —C(═O)—;

R¹⁰ represents halogen, hydroxy, C₁₋₄alkoxy or fluoroC₁₋₄alkoxy, orwhere p is 2, then two R¹⁰ groups may together represent an oxo (═O)group;

R¹¹ represents hydrogen, benzyl, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, COC₁₋₆alkyl, CO₂C₁₋₆alkyl or C₂₋₄alkylsubstituted by a C₁₋₄alkoxy or hydroxyl group;

R¹² represents hydrogen, fluorine, hydroxy, C₁₋₄alkoxy, or R¹² is linkedto R¹¹ such that there is formed a ring, the linkage —R¹²—R¹¹— beingselected from:

-   -   (a) —OC(O)—,    -   (b) —OS(O)₂—,    -   (c) -ZCH₂CH₂—,    -   (d) -ZCH₂CH₂CH₂—,    -   (e) -ZCH₂C(O)—,    -   (f) -ZCH₂CH₂C(O)—,    -   (g) -ZC(O)CH₂—,    -   (h) -ZC(O)CH₂CH₂—, and    -   (i) -ZCH₂C(O)CH₂—;        wherein Z represents O, NH or N(C₁₋₆alkyl);

m is 1 or 2; and

p is zero, 1 or 2.

One favoured group of compounds of the present invention are those ofthe formula (Ia) and pharmaceutically acceptable salts thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ as hereinbefore defined,and A, B, R¹⁰, R¹¹, m and n are as hereinbefore defined as for when W is

A preferred class of compounds of formula (Ia) is that wherein R¹ ishydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

Another preferred class of compounds of formula (Ia) is that wherein R²is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

A particularly preferred class of compounds of formula (Ia) is thatwherein R¹ is fluorine, chlorine, methyl or CF₃.

Another particularly preferred class of compounds of formula (Ia) isthat wherein R² is hydrogen, fluorine, chlorine, methyl or CF₃.

Also particularly preferred is the class of compounds of formula (Ia)wherein R³ is hydrogen, fluorine, chlorine, methyl or CF₃.

Preferably R¹ and R² are in the 3 and 5 positions of the phenyl ring.

More preferably R¹ is 3-fluoro, 3-chloro, 3-methyl or 3-CF₃.

More preferably R² is 5-fluoro, 5-chloro, 5-methyl or 5-CF₃.

More preferably R³ is hydrogen.

Most preferably R¹ is 3-F or 3-CF₃, R² is 5-CF₃ and R³ is hydrogen.

A further preferred class of compound of formula (Ia) is that wherein R⁴is fluorine or hydrogen.

Another preferred class of compounds of formula (Ia) is that wherein R⁵is hydrogen, fluorine, chlorine, bromine or CF₃.

Preferably R⁴ is hydrogen or 3-fluoro and R⁵ is hydrogen or 4-fluoro.

R⁶ is preferably C₁₋₄alkyl optionally substituted by hydroxy. Inparticular, R⁶ is preferably a methyl or hydroxymethyl group.

Another preferred class of compound of formula (Ia) is that wherein R⁷is hydrogen or methyl, and especially hydrogen.

A further preferred class of compound of formula (Ia) is that whereinone of R⁸ and R⁹ is hydrogen, and especially wherein R⁸ and R⁹ are bothhydrogen atoms.

Another preferred class of compound of formula (Ia) is that wherein R¹⁰represents hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy.

A further preferred class of compound of formula (Ia) is that whereinR¹¹ represents hydrogen or methyl.

A particularly preferred class of compound of formula (Ia) is thatwherein R¹⁰ represents hydroxy and R¹¹ represents hydrogen or methyl(especially hydrogen), where both R¹⁰ and R¹¹ are attached to the samecarbon atom, or alternatively R¹⁰ and R¹¹ together represent an oxogroup.

A further preferred class of compound of formula (Ia) is that wherein Ais CH₂ and B is an oxygen atom. When A is CH₂ and B is an oxygen atom itis preferred that the groups R¹⁰ and R¹¹ are not adjacent to B.

Another preferred class of compound of formula (Ia) is that wherein n is2 and m is 2.

Also preferred are the classes of compound of formula (Ia) wherein n is1 and m is 3; or n is 1 and m is 2; or n is 1 and m is 1.

One favoured group of compounds of the formula (Ia) are those of theformula (Iaa) and pharmaceutically acceptable salts thereof:

wherein

A¹ is fluorine or CF₃;

A² is fluorine or CF₃;

A³ is hydrogen or fluorine;

A⁴ is hydrogen, fluorine or bromine;

A⁵ is methyl or hydroxymethyl; and

A, B, R¹⁰ and R¹¹ are as defined in relation to formula (Ia).

Another favoured group of compounds of the formula (Ia) are those of theformula (Iab) and pharmaceutically acceptable salts thereof:

wherein

X represents CHOH or C═O;

R¹ is fluorine or trifluoromethyl;

R² is fluorine or trifluoromethyl;

R³ is methyl or hydroxymethyl;

R⁴ is hydrogen or fluorine; and

R⁵ is hydrogen or fluorine;

and pharmaceutically acceptable salts thereof.

A preferred class of compounds of formula (Iab) is that wherein R¹ istrifluoromethyl.

Another preferred class of compounds of formula (Iab) is that wherein R²is trifluoromethyl.

Also particularly preferred is the class of compounds of formula (Iab)wherein R³ is methyl.

A further preferred class of compound of formula (Iab) is that whereinR⁴ is fluorine.

Another preferred class of compounds of formula (Iab) is that wherein R⁵is hydrogen.

Another preferred class of compound of formula (Iab) is that wherein Xis CHOH.

One favoured group of compounds of the formula (Iab) are those of theformula (Iaba) and pharmaceutically acceptable salts thereof:

wherein

A¹ is hydrogen or fluorine, especially hydrogen; and

A² is hydrogen or fluorine, especially fluorine.

Another favoured group of the compounds of the present invention arethose of the formula (Ib) and pharmaceutically acceptable salts thereof:

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are hereinbefore defined; R¹⁰, R¹¹,R¹², m, n and p are as hereinbefore defined as for when W is

R⁸ represents halogen, C₁₋₆alkyl, CH₂OR^(c), CO₂R^(a) or CONR^(a)R^(b),or where q is 2, then two R⁸ groups may together represent an oxo (═O)group, where R^(a) and R^(b) are as previously defined and R^(c)represents hydrogen, C₁₋₆alkyl or phenyl; and

q is zero, 1 or 2.

A preferred class of compounds of formula (Ib) is that wherein R¹ ishydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

Another preferred class of compounds of formula (Ib) is that wherein R²is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

A particularly preferred class of compounds of formula (Ib) is thatwherein R¹ is fluorine, chlorine, methyl or CF₃.

Another particularly preferred class of compounds of formula (Ib) isthat wherein R² is hydrogen, fluorine, chlorine, methyl or CF₃.

Also particularly preferred is the class of compounds of formula (Ib)wherein R³ is hydrogen, fluorine, chlorine, methyl or CF₃.

Preferably R¹ and R² are in the 3 and 5 positions of the phenyl ring.

More preferably R¹ is 3-fluoro, 3-chloro, 3-methyl or 3-CF₃.

More preferably R² is 5-fluoro, 5-chloro, 5-methyl or 5-CF₃.

More preferably R³ is hydrogen.

Most preferably R¹ is 3-F or 3-CF₃, R² is 5-CF₃ and R³ is hydrogen.

A further preferred class of compound of formula (Ib) is that wherein R⁴is hydrogen or fluorine.

Another preferred class of compounds of formula (Ib) is that wherein R⁵is hydrogen, fluorine, chlorine or CF₃.

Preferably R⁴ is hydrogen or 3-fluoro and R⁵ is hydrogen or 4-fluoro.

R⁶ is preferably C₁₋₄alkyl optionally substituted by hydroxy. Inparticular, R⁶ is preferably a methyl or hydroxymethyl group. Mostespecially, R⁶ is a methyl group.

A further preferred class of compounds of formula (Ib) is that whereinR¹⁰ is hydrogen, C₁₋₄alkyl or a C₂₋₄alkyl group substituted by ahydroxyl or C₁₋₂alkoxy group.

Another preferred class of compounds of formula (Ib) is that wherein R¹¹is hydrogen, C₁₋₄alkyl, or a benzyl group.

Where R¹⁰ and R¹¹ are linked so that, together with the nitrogen atom towhich they are attached, they form a heteroaliphatic ring, suitablerings include azetidinyl, pyrrolidinyl, piperidinyl, morpholino,thiomorpholino, piperazino or a piperazino group substituted on thenitrogen atom by a C₁₋₄alkyl group or a C₂₋₄alkyl group substituted by ahydroxy or C₁₋₂alkoxy group. Particularly preferred heteroaliphaticrings formed by —NR¹⁰R¹¹ are azetidine, pyrrolidine, piperidine,morpholine, piperazine and N-methylpiperazine.

Another preferred class of compounds of formula (Ib) is that wherein R¹²is fluorine, hydroxy, methoxy or ethoxy or, where p is 2, then the twoR¹² groups together represent an oxo (═O) group.

Another preferred class of compounds of formula (Ib) is that wherein R⁸is methyl.

Another preferred class of compounds of formula (Ib) is that wherein mis zero or 1 and n is 1 or 2. Most preferably, m is zero and n is 2.

Yet another preferred class of compounds of formula (Ib) is that whereinp is zero.

A further preferred class of compounds of formula (Ib) is that wherein qis zero.

It will be appreciated that where one or two R¹² groups are present,each group may replace any of the hydrogen atoms in the (CH₂)_(m) and(CH₂)_(n) groups. Similarly, the —CH₂—NR¹⁰R¹¹ moiety may replace ahydrogen atom in either of the (CH₂)_(m) and (CH₂)_(n) groups.

One favoured group of compounds of the formula (Ib) are those of theformula (Iba) and pharmaceutically acceptable salts thereof:

wherein

A¹ is fluorine or CF₃;

A² is fluorine or CF₃;

A³ is fluorine or hydrogen;

A⁴ is fluorine or hydrogen;

A⁵ is methyl; and

R¹⁰, R¹¹, R¹², m, n and p are as defined in relation to formula (Ib).

Another favoured group of the compounds of the present invention arethose of the formula (Ic) and pharmaceutically acceptable salts thereof:

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as hereinbefore defined;A, B, R¹⁰, R¹¹, R¹², R¹³, m, p and q are as hereinbefore defined as forwhen W is

R⁸ represents halogen, C₁₋₆alkyl, CH₂OR^(c), CO₂R^(a) or CONR^(a)R^(b),or where n is 2, then two R⁸ groups may together represent an oxo (═O)group, where R^(a) and R^(b) are as previously defined and R^(c)represents hydrogen, C₁₋₆alkyl or phenyl; and

n is zero, 1 or 2.

A preferred class of compounds of formula (Ic) is that wherein R¹ ishydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

Another preferred class of compounds of formula (Ic) is that wherein R²is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

A particularly preferred class of compounds of formula (Ic) is thatwherein R¹ is fluorine, chlorine, methyl or CF₃.

Another particularly preferred class of compounds of formula (Ic) isthat wherein R² is hydrogen, fluorine, chlorine, methyl or CF₃.

Also particularly preferred is the class of compounds of formula (Ic)wherein R³ is hydrogen, fluorine, chlorine, methyl or CF₃.

Preferably R¹ and R² are in the 3 and 5 positions of the phenyl ring.

More preferably R¹ is 3-fluoro, 3-chloro, 3-methyl or 3-CF₃.

More preferably R² is 5-fluoro, 5-chloro, 5-methyl or 5-CF₃.

More preferably R³ is hydrogen.

Most preferably R¹ is 3-F or 3-CF₃, R² is 5-CF₃ and R³ is hydrogen.

A further preferred class of compound of formula (Ic) is that wherein R⁴is hydrogen or fluorine.

Another preferred class of compounds of formula (Ic) is that wherein R⁵is hydrogen, fluorine, chlorine or CF₃.

Preferably R⁴ is hydrogen or 3-fluoro and R⁵ is hydrogen or 4-fluoro.

R⁶ is preferably C₁₋₄alkyl optionally substituted by hydroxy. Inparticular, R⁶ is preferably a methyl or hydroxymethyl group. Mostespecially, R⁶ is a methyl group.

Another preferred class of compounds of formula (Ic) is that wherein R¹⁰is hydrogen, hydroxy, C₁₋₂alkyl substituted by hydroxy, C₁₋₄alkoxy(especially methoxy) or CO₂R^(e) (where R^(e) is hydrogen, methyl ethylor benzyl). Particularly preferred are compounds of formula (Ic) whereR¹⁰ is hydrogen.

A further preferred class of compounds of formula (Ic) is that whereinR¹¹ is hydrogen or C₁₋₄alkyl (especially methyl). Particularly preferredare compounds of formula (I) where R¹¹ is hydrogen.

R¹⁰ and R¹¹ are preferably attached to the same carbon atom thus forminga moiety of the formula CR¹⁰R¹¹. Where R¹⁰ and R¹¹ are attached to thesame carbon atom they may, in particular, together represent—C(O)OCH₂CH₂—.

In a further preferred class of compounds of formula (Ic), R¹²preferably represents hydrogen, methyl or ethyl.

Another preferred class of compounds of formula (Ic) is that wherein R⁸is methyl.

A further preferred class of compounds of formula (Ic) is that wherein nis zero.

A further preferred class of compounds of formula (Ic) is that wherein Ais NR¹² and B is S(O)_(q).

Preferably, q is zero.

One favoured group of compounds of the formula (Ic) are those of theformula (Ica) and pharmaceutically acceptable salts thereof:

wherein

A¹ is fluorine or CF₃;

A² is fluorine or CF₃;

A³ is fluorine or hydrogen;

A⁴ is fluorine or hydrogen;

A⁵ is methyl; and

A, B, R¹⁰ and R¹¹ are as defined in relation to formula (Ic).

Another favoured group of the compounds of the present invention arethose of the formula (Id) and pharmaceutically acceptable salts thereof:

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as hereinbefore defined;R¹⁰, R¹¹, m, n and p are as hereinbefore defined as for when W is

R⁸ represents halogen, C₁₋₆alkyl, CH₂OR^(c), CO₂R^(a) or CONR^(a)R^(b),or where q is 2, then two R⁸ groups may together represent an oxo (═O)group, where R^(a) and R^(b) are as previously defined and R^(c)represents hydrogen, C₁₋₆alkyl or phenyl; and

q is zero, 1 or 2.

A preferred class of compounds of formula (Id) is that wherein R¹ ishydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

Another preferred class of compounds of formula (Id) is that wherein R²is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

A particularly preferred class of compounds of formula (Id) is thatwherein R¹ is fluorine, chlorine, methyl or CF₃.

Another particularly preferred class of compounds of formula (Id) isthat wherein R² is hydrogen, fluorine, chlorine, methyl or CF₃.

Also particularly preferred is the class of compounds of formula (Id)wherein R³ is hydrogen, fluorine, chlorine, methyl or CF₃.

Preferably R¹ and R² are in the 3 and 5 positions of the phenyl ring.

More preferably R¹ is 3-fluoro, 3-chloro, 3-methyl or 3-CF₃.

More preferably R² is 5-fluoro, 5-chloro, 5-methyl or 5-CF₃.

More preferably R³ is hydrogen.

Most preferably R¹ is 3-F or 3-CF₃, R² is 5-CF₃ and R³ is hydrogen.

A further preferred class of compound of formula (Id) is that wherein R⁴is hydrogen or fluorine.

Another preferred class of compounds of formula (Id) is that wherein R⁵is hydrogen, fluorine, chlorine or CF₃.

Preferably R⁴ is hydrogen or 3-fluoro and R⁵ is hydrogen or 4-fluoro.

R⁶ is preferably C₁₋₄alkyl optionally substituted by hydroxy. Inparticular, R⁶ is preferably a methyl or hydroxymethyl group. Mostespecially, R⁶ is a methyl group.

Another preferred class of compounds of formula (Id) is that wherein R¹⁰is fluorine, hydroxy, methoxy or ethoxy or, where p is 2, then the twoR¹⁰ groups together represent an oxo (═O) group.

In a further preferred class of compounds of formula (Id), R¹¹preferably represents hydrogen, methyl or ethyl.

Another preferred class of compounds of formula (Id) is that wherein R⁸is methyl.

Another preferred class of compounds of formula (Id) is that wherein mis zero or 1 and n is zero or 1, and the sum total of m+n is 1. Mostpreferably, m is zero and n is 1.

A further preferred class of compound of formula (Id) is that wherein mis 2 and n is 1.

Yet another preferred class of compounds of formula (Id) is that whereinp is zero.

A further preferred class of compounds of formula (Id) is that wherein qis zero.

It will be appreciated that where one or two R¹⁰ groups are present,each group may replace any of the hydrogen atoms in the (CH₂)_(m) and(CH₂)_(n) groups.

One favoured group of compounds of the formula (Id) are those of theformula (Ida) and pharmaceutically acceptable salts thereof:

wherein

A¹ is fluorine or CF₃;

A² is fluorine or CF₃;

A³ is fluorine or hydrogen;

A⁴ is fluorine or hydrogen;

A⁵ is methyl; and

R¹⁰, R¹¹, m, n and p are as defined in relation to formula (Id).

Another favoured group of the compounds of the present invention arethose of formula (Ie) and pharmaceutically acceptable salts thereof:

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as hereinbefore defined;X Y, Z, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, m, n and p are as hereinbefore definedas for when W is

R⁸ represents halogen, C₁₋₆alkyl, CH₂OR^(c), CO₂R^(a) or CONR^(a)R^(b),or where q is 2, then two R⁸ groups may together represent an oxo (═O)group, where R^(a) and R^(b) are as previously defined and R^(c)represents hydrogen, C₁₋₆alkyl or phenyl; and

q is zero, 1 and 2.

A preferred class of compounds of formula (Ie) is that wherein X is—CH(OH)—.

Another preferred class of compounds of formula (Ie) is that wherein Yis —NR¹³R¹⁴ (wherein R¹³ and R¹⁴ are preferably hydrogen or C₁₋₄alkyl)or the group

wherein R¹⁰ and R¹¹ are preferably hydrogen and m is 1 or 2, andespecially 2.

A further preferred class of compounds of formula (Ie) is that wherein Zis O, S or NR¹², especially where R¹² is a C₁₋₄alkyl group, such asmethyl or ethyl.

A preferred class of compounds of formula (Ie) is that wherein R¹ ishydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

Another preferred class of compounds of formula (Ie) is that wherein R²is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

A particularly preferred class of compounds of formula (Ie) is thatwherein R¹ is fluorine, chlorine, methyl or CF₃.

Another particularly preferred class of compounds of formula (Ie) isthat wherein R² is hydrogen, fluorine, chlorine, methyl or CF₃.

Also particularly preferred is the class of compounds of formula (Ie)wherein R³ is hydrogen, fluorine, chlorine, methyl or CF₃.

Preferably R¹ and R² are in the 3 and 5 positions of the phenyl ring.

More preferably R¹ is 3-fluoro, 3-chloro, 3-methyl or 3-CF₃.

More preferably R² is 5-fluoro, 5-chloro, 5-methyl or 5-CF₃.

More preferably R³ is hydrogen.

Most preferably R¹ is 3-F or 3-CF₃, R² is 5-CF₃ and R³ is hydrogen.

A further preferred class of compound of formula (Ie) is that wherein R⁴is hydrogen or fluorine.

Another preferred class of compounds of formula (Ie) is that wherein R⁵is hydrogen, fluorine, chlorine or CF₃.

Preferably R⁴ is hydrogen or 3-fluoro and R⁵ is hydrogen or 4-fluoro.

R⁶ is preferably C₁₋₄alkyl optionally substituted by hydroxy. Inparticular, R⁶ is preferably a methyl or hydroxymethyl group. Mostespecially, R⁶ is a methyl group.

Another preferred class of compounds of formula (Ie) is that wherein R¹⁰is hydrogen, fluorine, hydroxy, methoxy or ethoxy and R¹¹ is hydrogen,or R¹⁰ and R¹¹ are both fluorine or R¹⁰ and R¹¹ together represent anoxo (═O) group.

Another preferred class of compounds of formula (Ie) is that wherein R⁸is methyl.

A further preferred class of compounds of formula (Ie) is that whereinR¹² is methyl, ethyl, acetyl, methoxycarbonyl or ethoxycarbonyl.

Another preferred class of compounds of formula (Ie) is that wherein R¹³and R¹⁵ each independently represent hydrogen or C₁₋₄alkyl, andespecially, methyl.

Another preferred class of compounds of formula (Ie) is that wherein mis 2.

A further preferred class is that wherein m is 2 and n is 2.

Yet another preferred class of compounds of formula (Ie) is that whereinp is 1.

A further preferred class of compounds of formula (Ie) is that wherein qis zero.

It will be appreciated that R¹⁰ and R¹¹ may replace any of the hydrogenatoms in the (CH₂)_(m) and (CH₂)_(p) groups in the rings to which theyare attached.

One favoured group of compounds of the formula (Ie) are those of theformula (Iea) and pharmaceutically acceptable salts thereof:

wherein

A¹ is fluorine or CF₃;

A² is fluorine or CF₃;

A³ is fluorine or hydrogen;

A⁴ is fluorine or hydrogen;

A⁵ is methyl; and

X and Y are as defined in relation to formula (Ie).

Another favoured group of compounds of the present invention are thoseof formula (If) and pharmaceutically acceptable salts thereof:

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as hereinbefore defined;X, R¹⁰, R¹¹, R¹², m and p are as hereinbefore defined as for when W is

R⁸ represents halogen, C₁₋₆alkyl, CH₂OR^(c), CO₂R^(a) or CONR^(a)R^(b),or where q is 2, then two R⁸ groups may together represent an oxo (═O)group, where R^(a) and R^(b) are as previously defined and R^(c)represents hydrogen, C₁₋₆alkyl or phenyl; and

q is zero, 1 or 2.

A preferred class of compounds of formula (If) is that wherein R¹ ishydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

Another preferred class of compounds of formula (If) is that wherein R²is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, halogen or CF₃.

A particularly preferred class of compounds of formula (If) is thatwherein R¹ is fluorine, chlorine, methyl or CF₃.

Another particularly preferred class of compounds of formula (If) isthat wherein R² is hydrogen, fluorine, chlorine, methyl or CF₃.

Also particularly preferred is the class of compounds of formula (If)wherein R³ is hydrogen, fluorine, chlorine, methyl or CF₃.

Preferably R¹ and R² are in the 3 and 5 positions of the phenyl ring.

More preferably R¹ is 3-fluoro, 3-chloro, 3-methyl or 3-CF₃.

More preferably R² is 5-fluoro, 5-chloro, 5-methyl or 5-CF₃.

More preferably R³ is hydrogen.

Most preferably R¹ is 3-F or 3-CF₃, R² is 5-CF₃ and R³ is hydrogen.

A further preferred class of compound of formula (If) is that wherein R⁴is hydrogen or fluorine.

Another preferred class of compounds of formula (If) is that wherein R⁵is hydrogen, fluorine, chlorine or CF₃.

Preferably R⁴ is hydrogen or 3-fluoro and R⁵ is hydrogen or 4-fluoro.

R⁶ is preferably C₁₋₄alkyl optionally substituted by hydroxy. Inparticular, R⁶ is preferably a methyl or hydroxymethyl group. Mostespecially, R⁶ is a methyl group.

Another preferred class of compounds of formula (If) is that wherein R¹⁰is fluorine, hydroxy, methoxy or ethoxy or, where p is 2, then the twoR¹⁰ groups together represent an oxo (═O) group.

In a further preferred class of compounds of formula (If), R¹¹preferably represents hydrogen, methyl, ethyl or CO₂-tert-butyl.

Another preferred class of compounds of formula (If) is that wherein R⁸is methyl.

A further preferred class of compound of formula (If) is that wherein Xis —CHR¹²—.

In particular, R¹² is preferably hydrogen or hydroxy.

Where R¹² is linked to R¹¹ such that there is formed a ring, the linkage—R¹²—R¹¹— is preferably selected from:

-   -   (a) —OC(O)—,    -   (b) —OS(O)₂—,    -   (c) -ZCH₂CH₂—,    -   (d) -ZCH₂C(O)—,    -   (e) -ZC(O)CH₂—,        wherein Z represents O, NH or N(C₁₋₆alkyl). Most especially,        where R¹² is linked to R¹¹ such that there is formed a ring, the        linkage —R¹²—R¹¹— is preferably —OC(O)—.

Another preferred class of compounds of formula (If) is that wherein mis 1.

Yet another preferred class of compounds of formula (If) is that whereinp is zero.

A further preferred class of compounds of formula (If) is that wherein qis zero.

It will be appreciated that where one or two R¹⁰ groups are present,each group may replace any of the hydrogen atoms in the (CH₂)_(m)groups.

One favoured group of compounds of the present invention are those ofthe formula (Ifa) and pharmaceutically acceptable salts thereof:

wherein

A¹ is fluorine or CF₃;

A² is fluorine or CF₃;

A³ is fluorine or hydrogen;

A⁴ is fluorine or hydrogen;

A⁵ is methyl; and

X, R¹⁰, R¹¹, m and p are as defined in relation to formula (If).

When any variable occurs more than one time in formula (I) or in anysubstituent, its definition on each occurrence is independent of itsdefinition at every other occurrence.

As used herein, the term “alkyl” or “alkoxy” as a group or part of agroup means that the group is straight or branched. Examples of suitablealkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyland t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

As used herein, the terms “fluoroC₁₋₆alkyl” and “fluoroC₁₋₆alkoxy” meana C₁₋₆alkyl or C₁₋₆alkoxy group in which one or more (in particular, 1to 3) hydrogen atoms have been replaced by fluorine atoms. Similarly,the term “fluoroC₁₋₄alkyl” means a C₁₋₄alkyl group in which one or more(in particular 1 to 3) hydrogen atoms have been replaced by fluorineatoms. Particularly preferred are fluoroC₁₋₃alkyl and fluoroC₁₋₃alkoxygroups, for example, CF₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, OCF₃, OCH₂CH₂F,OCH₂CHF₂ or OCH₂CF₃, and most especially CF₃, OCF₃ and OCH₂CF₃.

The cycloalkyl groups referred to herein may represent, for example,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitablecycloalkylalkyl group may be, for example, cyclopropylmethyl.

Similarly cycloalkoxy groups referred to herein may represent, forexample, cyclopropoxy or cyclobutoxy.

As used herein, the terms “alkenyl” and “alkynyl” as a group or part ofa group mean that the group is straight or branched. Examples ofsuitable alkenyl groups include vinyl and allyl. A suitable alkynylgroup is propargyl.

When used herein the term “halogen” means fluorine, chlorine, bromineand iodine. The most apt halogens are fluorine and chlorine of whichfluorine is preferred, unless otherwise stated.

Specific compounds within the scope of this invention include:

-   (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;-   (4S)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;-   (4R)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;-   (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;-   8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4    fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane;-   8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran-4-yl)]methyl-1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane;-   8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran-4-yl)]methyl-2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane;-   8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1-oxa-8-aza-spiro[4.5]decane;-   8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane;-   8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyranyl]methyl-2-oxa-8-aza-spiro[4.5]decane;-   8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane;-   8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1-oxa-8-aza-spiro[4.5]decane;-   8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane;-   8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-one;-   (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyranyl]methyl-2-oxa-4-methyl-8-aza-spiro[4.5]decan-4-ol;    and pharmaceutically acceptable salts thereof.

Specific compounds within the scope of this invention also include:

-   (4R)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;-   (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-4-ethynyl-8-aza-spiro[4.5]decan-4-ol;-   (8S)-2-[((2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenyl)tetrahydro-2H-pyran-4-yl)methyl]-6-oxa-2-azaspiro[3.4]octan-8-ol;-   (8R)-2-[((2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-6-oxa-2-azaspiro[3.4]octan-8-ol;-   (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyltetrahydropyran-4-yl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol;-   (4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-4-ol;-   (4R*)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyranyl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol;-   (4S*)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyranyl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol;-   (4R)-8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-4-methoxy-2-oxa-8-azaspiro[4.5]decane;-   (4R)-8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)tetrahydro-2H-pyranyl)methyl]-4-methoxy-2-oxa-8-azaspiro[4.5]decane;-   8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-1-oxa-8-azaspiro[4.5]decan-3-ol;-   8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-1-oxa-8-azaspiro[4.5]decan-3-one;    and pharmaceutically acceptable salts thereof.

Further specific compounds within the scope of this invention include:

-   (2R or S,5R or    S)-5-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)tetrahydro-N-(phenylmethyl)-2-furanmethanamine;-   (2S or R,5R or    S)-5-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)tetrahydro-N-(phenylmethyl)-2-furanmethanamine;-   (2R or S,5R or    S)-5-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyranyl)tetrahydro-2-furanmethanamine;-   (2S or R,5R or    S)-5-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyranyl)-N,N-diethyltetrahydro-2-furanmethanamine;    and pharmaceutically acceptable salts thereof.

Specific compounds within the scope of this invention also include:

-   (3R or    S)-3-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)thiomorpholine;    and-   (3S or    R)-3-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)thiomorpholine;    and pharmaceutically acceptable salts thereof.

Further specific compounds within the scope of this invention include:

-   (2S)-2-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-methylazetidine;-   (2R)-2-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-methylazetidine;-   4-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)piperidin-4-ol;-   4-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-cyclopropylpiperidin-4-ol;    and-   4-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-(1-methylethyl)piperidin-4-ol;    and pharmaceutically acceptable salts thereof.

Specific compounds within the scope of this invention also include:

-   (αR or    S)-α-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy)}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-piperidineethanol;-   (αS or    R)-α-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-piperidineethanol;    and-   (αR or    S,2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-α-[(dimethylamino)methyl]-3-phenyl-2H-pyran-4-methanol;    and pharmaceutically acceptable salts thereof.

Further specific compounds within the scope of this invention include:

-   1,1-dimethylethyl(2R or S)-2-[(R or    S)-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)hydroxymethyl]-1-pyrrolidinecarboxylate;-   (1R or S, 7aR or    S)-1-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one;    and-   (2R,3R,4R,αR or S)-α-[(2R or    S)-2-pyrrolidinyl]-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol;    and pharmaceutically acceptable salts thereof.

In a further aspect of the present invention, the compounds of formula(I) may be prepared in the form of a pharmaceutically acceptable salt,especially an acid addition salt.

For use in medicine, the salts of the compounds of formula (I) will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of the compound according to the invention with a solution ofa pharmaceutically acceptable acid such as hydrochloric acid, fumaricacid, p-toluenesulfonic acid, maleic acid, succinic acid, acetic acid,citric acid, tartaric acid, carbonic acid, phosphoric acid or sulfuricacid. Salts of amine groups may also comprise quaternary ammonium saltsin which the amino nitrogen atom carries a suitable organic group suchas an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include metal salts suchas alkali metal salts, e.g. sodium or potassium salts; and alkalineearth metal salts, e.g. calcium or magnesium salts.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion exchange resin.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the “parent drug” or “parent molecule”)that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxylic, phosphoric or sulfate ester, or reduction oroxidation of a susceptible functionality.

The present invention includes within its scope solvates of thecompounds of formula (I) and salts thereof, for example, hydrates.

The compounds according to the invention have at least three asymmetriccentres, and may accordingly exist both as enantiomers and asdiastereoisomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The preferred compounds of the formulae (Ia) and (Iaa) will have thestereochemistry of the 2-, 3-, 4 and 8-positions as shown in formulae(Iac) and (Iad)

It will be appreciated that the preferred definitions of the varioussubstituents recited herein may be taken alone or in combination and,unless otherwise stated, apply to the generic formula for compounds ofthe present invention as well as to the preferred classes of compoundrepresented by formula (Iaa), formula (Iac) and formula (Iad).

The preferred compounds of the formulae (Iab) and (Iaba) will have thestereochemistry of the 2-, 3-, 4 and 8-positions as shown in formulae(Iabb) and (Iabc)

It will be appreciated that the preferred definitions of the varioussubstituents recited herein may be taken alone or in combination and,unless otherwise stated, apply to the generic formula for compounds ofthe present invention as well as to the preferred classes of compoundrepresented by formula (Iaba), formula (Iabb) and formula (Iabc).

The preferred compounds of the formulae (Ib), (Iba), (Id), (Ida), (Ie),(Iea), (If) and (Ifa) will have the stereochemistry of the 2-, 3-, 4 and8-positions as shown in formula (Ig) and formula (Ih)

It will be appreciated that the preferred definitions of the varioussubstituents recited herein may be taken alone or in combination and,unless otherwise stated, apply to the generic formula for compounds offormulae (Ib), (Id), (Ie) and (If) as well as to the preferred classesof compound represented by formulae (Iba), (Ida), (Iea), (Ifa), (Ig) and(Ih).

The preferred compounds of the formula (Ic) and (Ica) will have thestereochemistry of the 2-, 3-, 4 and 8-positions as shown in formula(Icb) and formula (Icc)

It will be appreciated that the preferred definitions of the varioussubstituents recited herein may be taken alone or in combination and,unless otherwise stated, apply to the generic formula for compounds offormula (Ic) as well as to the preferred classes of compound representedby formula (Ica), formula (Icb) and formula (Icc).

The present invention further provides pharmaceutical compositionscomprising one or more compounds of formula (I) in association with apharmaceutically acceptable carrier or excipient.

Preferably the compositions according to the invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,solutions or suspensions, or suppositories, for oral, parenteral orrectal administration, or administration by inhalation or insufflation.Oral compositions such as tablets, pills, capsules or wafers areparticularly preferred.

A more detailed description of pharmaceutical compositions that aresuitable for the formulation of compounds of the present invention isdisclosed in U.S. Pat. No. 6,071,927, the content of which isincorporated herein by reference (see in particular, column 8, line 50to column 10, line 4).

The present invention further provides a process for the preparation ofa pharmaceutical composition comprising a compound of formula (I), whichprocess comprises bringing a compound of formula (I) into associationwith a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity. Acomprehensive listing of clinical conditions, uses and methods oftreatment for which the compounds of the present invention will beuseful is disclosed in U.S. Pat. No. 6,071,927, the content of which isincorporated herein by reference (see, in particular, column 10, line 14to column 22, line 18).

In particular, the compounds of the present invention are useful in thetreatment of a variety of disorders of the central nervous system. Suchdisorders include mood disorders, such as depression or moreparticularly depressive disorders, for example, single episodic orrecurrent major depressive disorders and dysthymic disorders, or bipolardisorders, for example, bipolar I disorder, bipolar II disorder andcyclothymic disorder, and anxiety disorders, such as panic disorder withor without agoraphobia, agoraphobia without history of panic disorder,specific phobias, for example, specific animal phobias, social phobias,obsessive-compulsive disorder, stress disorders including post-traumaticstress disorder and acute stress disorder, and generalised anxietydisorders.

The compounds of the present invention are also particularly useful inthe treatment of nociception and pain. Diseases and conditions in whichpain predominates, include soft tissue and peripheral damage, such asacute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletalpain, particularly after trauma, spinal pain, myofascial pain syndromes,headache, migraine, episiotomy pain, and burns.

The compounds of the present invention are also particularly useful inthe treatment of respiratory diseases, particularly those associatedwith excess mucus secretion, such as chronic obstructive airwaysdisease, bronchopneumonia, chronic bronchitis, cystic fibrosis andasthma, adult respiratory distress syndrome, and bronchospasm; in thetreatment of inflammatory diseases such as inflammatory bowel disease,psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritusand sunburn; and in the treatment of allergic disorders such as eczemaand rhinitis.

The compounds of the present invention are also particularly useful inthe treatment of gastrointestinal (GI) disorders, including inflammatorydisorders and diseases of the GI tract such as ulcerative colitis,Crohn's disease and irritable bowel syndrome.

The compounds of the present invention are also particularly useful inthe treatment of emesis, including acute, delayed or anticipatoryemesis, such as emesis induced by chemotherapy, radiation, toxins,pregnancy, vestibular disorders, motion, surgery, migraine, andvariations in intercranial pressure. Most especially, the compounds offormula (I) are of use in the treatment of emesis induced byantineoplastic (cytotoxic) agents, including those routinely used incancer chemotherapy; by radiation including radiation therapy such as inthe treatment of cancer; and in the treatment of post-operative nauseaand vomiting.

The excellent pharmacological profile of the compounds of the presentinvention offers the opportunity for their use in therapy at low dosesthereby minimising the risk of unwanted side effects.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg per day.

For example, in the treatment of conditions involving theneurotransmission of pain sensations, a suitable dosage level is about0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day,and especially about 0.005 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

In the treatment of emesis, a suitable dosage level is about 0.001 to 10mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially0.01 to 3 mg/kg per day. The compounds may be administered on a regimenof 1 to 4 times per day, preferably once or twice per day.

In the treatment of psychiatric disorders, a suitable dosage level isabout 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg perday, and especially 0.01 to 3 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

It will be appreciated that the amount of a compound of formula (I)required for use in any treatment will vary not only with the particularcompounds or composition selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

As used herein, the term “treatment” includes prophylactic use toprevent the occurrence or recurrence of any of the aforementionedconditions.

According to a general process (Aa), compounds of formula (Ia) may beprepared by the reaction of a compound of formula (IIa)

wherein LG is a suitable leaving group such as an alkyl- orarylsulfonyloxy group (e.g. mesylate or tosylate) or a halogen atom(e.g. bromine, chlorine or iodine); by reaction with an amine of formula(IIIa)

The reaction is preferably effected in the presence of a base, forexample, an alkali metal carbonate, such as potassium carbonate, in asuitable organic solvent such as acetonitrile. The reaction ideally isperformed at an elevated temperature, for example, between 40° C. and80° C., especially between 50° C. and 70° C.

A particularly preferred compound of formula (IIa) is that wherein thegroup LG is mesylate, i.e. the group —OSO₂CH₃, which compound isprepared by reaction of the corresponding methanol with methanesulfonylchloride in the presence of a base, such as triethylamine, andoptionally a catalyst such as 4-N,N-dimethylaminopyridine. The reactionis conveniently effected in a solvent such as a halogenated hydrocarbon,for example, dichloromethane.

Using general process (Aa), compounds of formula (Iab) may be preparedby the reaction of a compound of formula (IIab)

wherein LG is a suitable leaving group such as an alkyl- orarylsulfonyloxy group (e.g. mesylate or tosylate) or a halogen atom(e.g. bromine, chlorine or iodine); by reaction with an amine of formula(IIIab)

A particularly preferred compound of formula (IIab) is that wherein thegroup LG is mesylate, i.e. the group —OSO₂CH₃, which compound isprepared by reaction of the corresponding methanol with methanesulfonylchloride in the presence of a base, such as triethylamine, andoptionally a catalyst such as 4-N,N-dimethylaminopyridine. The reactionis conveniently effected in a solvent such as a halogenated hydrocarbon,for example, dichloromethane.

According to another general process (Ba), compounds of formula (Ia) maybe prepared by the reaction of an amine of formula (IIIa) with acompound of formula (IVa)

in the presence of a reducing agent, for example, sodiumtriacetoxyborohydride or sodium cyanoborohydride. The reaction isconveniently effected in a suitable solvent such as a halogenatedhydrocarbon, for example, 1,2-dichloroethane, conveniently at about roomtemperature.

Further details of suitable procedures will be found in the accompanyingExamples.

Using general process (Ba), compounds of formula (Iab) may be preparedby the reaction of an amine of formula (IIIab) with a compound offormula (IVab)

in the presence of a reducing agent, for example, sodiumtriacetoxyborohydride or sodium cyanoborohydride. The reaction isconveniently effected in a suitable solvent such as a halogenatedhydrocarbon, for example, 1,2-dichloroethane, conveniently at about roomtemperature.

Further details of suitable procedures will be found in the accompanyingExamples.

Compounds of formulae (IIa) and (IIab) may be prepared by conventionalmethods such as those described in International (PCT) PatentPublication No. WO 00/56727.

Compounds of formula (IIIa), and compounds of formula (IIIab) wherein Xis CHOH, may be prepared from a suitably substituted precursorpiperidine compound, for instance, as shown in Scheme 1 (in which R is,for example, a C₁₋₆alkyl group, such as an ethyl group, and P is anamino protecting group, such as a benzyloxycarbonyl group):

An alternative (asymmetric) synthesis of compounds of formula (IIIa),and compounds of formula (IIIab) wherein X is CHOH, is shown in Scheme2:

A further alternative (asymmetric) synthesis of compounds of formula(Ia), and compounds of formula (IIIab) wherein X is CHOH, is shown inScheme 3:

It will be appreciated that numerous other routes will be readilyapparent to one of ordinary skill in the art, the route of choicedepending upon the particular spiro-amine that is desired. Themethodology described herein may be adapted accordingly. Thus, forinstance, in addition to the processes outlined in Schemes 1, 2 and 3above, amines of formula (IIIa) may be prepared by other methods thatwould be readily apparent to one of ordinary skill in the art. Forexample, methods for the preparation of the spirocyclic amines areprovided in the literature—see for instance, Bioorg. Med. Chem. Lett.,12 (2002) 1759-62 and International (PCT) Patent Publication No. WO01/87838.

Compounds of formulae (IVa) and (IVab) may be prepared by conventionalmethods such as those described in International (PCT) PatentPublication No. WO 00/56727, for instance, by the oxidation of acorresponding vinyl compound using oxygen and ozone. The reaction isconveniently effected at a reduced temperature, such as at about −78°C., in the presence of an organic solvent such as an alcohol, forexample, methanol, or a halogenated hydrocarbon, for example,dichloromethane, or a mixture thereof. Treatment with dimethylsulfideliberates the desired aldehyde.

According to a general process (Ab), compounds of formula (Ib) in whichm is zero and n is 2 or 3 may be prepared by the cyclization of acompound of formula (IIb) in the presence of an amine of the formulaR¹⁰R¹¹NH:

wherein LG¹ and LG² are independently leaving groups, such as mesylate,tosylate, brosylate, nosylate or triflate. Conveniently, LG¹ and LG² maybe the same or different, for instance LG¹ may be mesylate whilst LG²may be tosylate.

The reaction is effected at an elevated temperature, for example,between 120° and 160° C., preferably at about 140° C., in a suitablesolvent, such as an alcohol, for instance, methanol.

According to another general process (Bb), compounds of formula (Ib) inwhich m is 1 and n is 1 or 2 may be prepared by the cyclization of acompound of formula (Ib) in the presence of an amine of the formulaR¹⁰R¹¹NH:

wherein LG¹ and LG² are as previously defined.

The reaction is effected at an elevated temperature, for example,between 120° and 160° C., preferably at about 140° C., in a suitablesolvent, such as an alcohol, for instance, methanol.

According to another general process (Cb), compounds of formula (Ib) inwhich m is 2 and n is 2 may be prepared by the cyclization of a compoundof formula (IVb) in the presence of an amine of the formula R¹⁰R¹¹NH:

wherein LG¹ and LG² are as previously defined.

The reaction is effected at an elevated temperature, for example,between 120° and 160° C., preferably at about 140° C., in a suitablesolvent, such as an alcohol, for instance, methanol.

Further details of suitable procedures will be found in the accompanyingExamples.

Compounds of formula (IIb) may be prepared from a compound of formula(Vb)

by reaction with a dihydroxylating agent such as AD-mix-α or AD-mix-β(see Aldrichimica Acta 1994, 27, 70), followed by conversion of theprimary alcohol to the LG² group.

The dihydroxylation reaction is conveniently effected at roomtemperature in a solvent such as an alcohol, for instance, tert-butanol,or water, or more preferably a mixture thereof.

The conversion of the primary alcohol to the LG² group is effected in aconventional manner, for instance by reaction with the appropriatesulfonyl chloride in the presence of a base, such as triethylamine. Thereaction is conveniently effected in a solvent such as a halogenatedhydrocarbon, for example, dichloromethane, at a reduced temperature,such as below −20° C., and then at room temperature. Addition ofdibutyltin oxide to the reaction conveniently promotes formation of theleaving group on the primary alcohol group.

Similarly, compounds of formula (IIIb) may be prepared from a compoundof formula (VIb)

Likewise, compounds of formula (IVb) may be prepared from a compound offormula (VIIb)

Compounds of formula (Vb) may be prepared by reaction of an aldehyde offormula (VIIIb)

with a suitable Grignard reagent, such as CH₂—CH(CH₂)_(n)CH₂MgBr orCH₂═CH(CH₂)_(n)CH₂MgCl, followed by conversion of the secondary alcoholto the LG¹ group.

The Grignard reaction is effected in the presence of a suitable solventsuch as an ether, for instance, tetrahydrofuran, at a reducedtemperature, for example, below −40° C., and preferably at about −78° C.

The conversion of the secondary alcohol to the LG¹ group is effected ina conventional manner, for instance by reaction with the appropriatesulfonyl chloride in the presence of a base, such as triethylamine. Thereaction is conveniently effected in a solvent such as a halogenatedhydrocarbon, for example, dichloromethane, at a reduced temperature,such as below −20° C., and then at room temperature.

Compounds of formula (VIIIb) may be prepared by conventional methodssuch as those described in International (PCT) Patent Publication No. WO00/56727, for instance, by the oxidation of a corresponding vinylcompound using oxygen and ozone. The reaction is conveniently effectedat a reduced temperature, such as at about −78° C., in the presence ofan organic solvent such as an alcohol, for example, methanol, or ahalogenated hydrocarbon, for example, dichloromethane, or a mixturethereof. Treatment with dimethylsulfide liberates the desired aldehyde.

Compounds of formula (VIb) may be prepared from a compound of formula(IXb)

by reaction with a reducing agent such as a borohydride, for example,sodium borohydride, followed by conversion of the alcohol thus formedinto the LG¹ group as previously described. The reduction is effected ina suitable solvent such as an alcohol, for example, ethanol, at areduced temperature such as between −10° C. and +5° C., preferably atabout 0° C.

Similarly, compounds of formula (VIIb) may be prepared from a compoundof formula (Xb)

Compounds of formula (IXb) may be prepared from a compound of formula(XIb)

by reaction with, for example, an ylide such as that prepared fromPh₃P⁺CH₂OMeCl⁻ in the presence of a strong base such as lithiumdiisopropylamide and a suitable solvent such as an ether, for example,tetrahydrofuran, followed by treatment with an acid such as a mineralacid, for example, aqueous hydrochloric acid.

Compounds of formula (XIb) may be prepared from a compound of formula(XIIb)

by a suitable oxidation reaction, such as a Swern oxidation usingdimethylsulfoxide and oxalyl chloride, and a base such as triethylamine.The reaction is conveniently effected in a solvent such as a halogenatedhydrocarbon, for example, dichloromethane, at a reduced temperature, forexample at about −78° C., and then warming to room temperature.

Compounds of formula (XIIb) may be prepared from a compound of formula(VIIIb) by reaction with a suitable Grignard reagent as previouslydescribed.

Compounds of formula (Xb) may be prepared from a compound of formula(IXb) under the conditions described above for the preparation of acompound of formula (IXb).

According to a general process (Ac), compounds of formula (Ic) in whichA is NR¹² and B is S(O)_(q) (where q is zero) may be prepared by thereaction of a compound of formula (IIc) in the presence of an amine ofthe formula R¹²NH₂:

wherein LG¹ and LG² are independently leaving groups, such as mesylate,tosylate, brosylate, nosylate or triflate. Conveniently, LG¹ and LG² maybe the same or different, for instance LG¹ is may be mesylate whilst LG²may be tosylate.

The reaction is effected at an elevated temperature, for example,between 120° and 160° C., preferably at about 140° C., in a suitablesolvent, such as an alcohol, for instance, methanol.

According to another general process (Bc), compounds of formula (Ic) inwhich A is S(O)_(q) (where q is zero) and B is NR¹² may be prepared froma compound of formula (IIIc)

wherein LG¹ and LG² are as previously defined, and P is an amineprotecting group, by reaction with sodium sulfide, followed, if desired,by deprotection of the amine and subsequent alkylation of the amine tovary the group R¹².

The cyclization reaction is effected in a suitable solvent such asacetone at an elevated temperature, for example, at the refluxtemperature of the solvent.

A particularly suitable amine protecting group is an alkoxycarbonylgroup such as tert-butoxycarbonyl, which is conveniently removed bytreatment with trifluoroacetic acid in a solvent such as a halogenatedhydrocarbon, for example, dichloromethane, at a reduced temperature,such as between −10° C. and +5° C., for example, at about 0° C.

Further details of suitable procedures will be found in the accompanyingExamples.

Compounds of formula (IIc) may be prepared from a corresponding diol offormula (IVc)

The conversion of the alcohols to the LG¹ and LG² groups is effected ina conventional manner, for instance by reaction with the appropriatesulfonyl chloride in the presence of a base, such as triethylamine. Thereaction is conveniently effected in a solvent such as a halogenatedhydrocarbon, for example, dichloromethane, at a reduced temperature,such as below −20° C., and then at room temperature.

Similarly, compounds of formula (IIIc) may be prepared from acorresponding diol of formula (Vc)

Compounds of formula (IVc) may be prepared from an epoxide of formula(VIc)

by reaction with HOCH₂CH₂SH in the presence of a base such as ahydroxide, for instance, potassium hydroxide. The reaction isconveniently effected in a solvent such as an alcohol, for exampleisopropanol, at an elevated temperature, for example at the refluxtemperature of the solvent.

Compounds of formula (Vc) may be prepared from an epoxide of formula(VIc) by reaction with HOCH₂CH₂NH₂ in a solvent such as an alcohol, forexample methanol, at an elevated temperature, for example at the refluxtemperature of the solvent, followed by protection of the secondaryamine, for example with di-tert-butyl dicarbonate. This reaction isconveniently effected in a solvent such as a halogenated hydrocarbon,for example, dichloromethane, at room temperature.

Compounds of formula (VIc) may be prepared from a compound of formula(VIIc)

by reaction with trimethylsulfonium iodide in the presence of a basesuch as sodium hydride. The reaction is conveniently effected in asuitable solvent such as dimethylsulfoxide or an ether, such astetrahydrofuran, or a mixture thereof, at a reduced temperature between−10° C. and +5° C., for example, at about 0° C.

Compounds of formula (VIIc) may be prepared by conventional methods suchas those described in International (PCT) Patent Publication No. WO00/56727, for instance, by the oxidation of a corresponding vinylcompound of formula (VIIIc)

using oxygen and ozone. The reaction is conveniently effected at areduced temperature, such as at about −78° C., in the presence of anorganic solvent such as an alcohol, for example, methanol, or ahalogenated hydrocarbon, for example, dichloromethane, or a mixturethereof. Treatment with dimethylsulfide liberates the desired aldehyde.

In an alternative method, compounds of formula (VIc) may be prepareddirectly from a compound of formula (VIIIc) by an epoxidization reactionusing a peracid, for example, m-chloroperbenzoic acid. The reaction iseffected in a solvent such as a halogenated hydrocarbon, for example,dichloromethane, conveniently at room temperature.

Compounds of formula (VIIIc) are known compounds or may be prepared byconventional methods such as those described in International (PCT)Patent Publication Nos. WO 00/56727 and WO 02/16344.

According to a general process (Ad), compounds of formula (Id) in whichm is zero and n is 1 may be prepared by the cyclization of a compound offormula (Id) in the presence of an amine of the formula R¹¹NH₂:

wherein LG¹ and LG² are independently leaving groups, such as mesylate,tosylate, brosylate, nosylate or triflate. Conveniently, LG¹ and LG² maybe the same or different, for instance LG¹ and LG² may both be mesylate.

The reaction is effected at an elevated temperature, for example,between 120° and 160° C., preferably at about 140° C., in a suitablesolvent, such as an alcohol, for instance, methanol.

According to another general process (Bd), compounds of formula (Id) inwhich m is 1 or 2 and n is zero may be prepared by the cyclization of acompound of formula (IIId) in the presence of an amine of the formulaR¹¹NH₂:

wherein LG¹ and LG² are as previously defined.

The reaction is effected at an elevated temperature, for example,between 120° and 160° C., preferably at about 140° C., in a suitablesolvent, such as an alcohol, for instance, methanol.

According to another general process (Cd), compounds of formula (Id) inwhich m is 2 and n is 1 may be prepared by the cyclization of a compoundof formula (IVd) in the presence of an amine of the formula R¹¹NH₂:

wherein LG¹ and LG² are as previously defined.

The reaction is effected at an elevated temperature, for example,between 120° and 160° C., preferably at about 130° C., in a suitablesolvent, such as an alcohol, for instance, methanol.

With regard to general processes (Bd) and (Cd), it will be appreciatedby one of ordinary skill in the art that the geminal hydroxyl group canbe removed using conventional methodology.

Further details of suitable procedures will be found in the accompanyingExamples.

Compounds of formula (IId) may be prepared from a compound of formula(Vd)

The conversion of the primary and secondary alcohols to the LG¹ and LG²groups is effected in a conventional manner, for instance by reactionwith the appropriate sulfonyl chloride (e.g. methanesulfonyl chloride)in the presence of a base, such as triethylamine. The reaction isconveniently effected in a solvent such as a halogenated hydrocarbon,for example, dichloromethane, at a reduced temperature, such as below−20° C., and then at room temperature.

Similarly, compounds of formula (IIId) may be prepared from a compoundof formula (VId)

Likewise, compounds of formula (IVd) may be prepared from a compound offormula (VIId)

Compounds of formula (Vd) may be prepared from a compound of formula(VIIId)

by reaction with ozone, followed by treatment with sodium borohydride.

The ozonolysis reaction is effected at a reduced temperature, forexample, below −40° C., and preferably at about −78° C., in a suitablesolvent such as a halogenated hydrocarbon, for example, dichloromethane,or an alcohol, for example, methanol, or a mixture thereof.

Similarly, compounds of formula (VId) may be prepared from a compound offormula (IXd)

where Q is —CH═ (for compounds where m is 1) or —CH₂CH═ (for compoundswhere m is 2).

Likewise, compounds of formula (VIId) may be prepared from a compound offormula (Xd)

Compounds of formula (VIIId) may be prepared by reaction of a compoundof formula (XId)

with a suitable Grignard reagent, such as CH₂═CHCH₂MgBr orCH₂═CHCH₂MgCl. The reaction is effected in the presence of a suitablesolvent such as an ether, for instance, diethyl ether ortetrahydrofuran, at a reduced temperature, for example, below −40° C.,and preferably at about −78° C.

The stereochemistry of the intermediate of formula (Vdd) may be directedby the inclusion in the Grignard reaction ofchlorobis[(1S,2R,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]borane((+)-DIP-Cl) orchlorobis[(1R,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]borane((−)-DIP-Cl) which is conveniently pre-mixed with the allyl Grignardreagent at a reduced temperature, for instance, at about −40° C., andwarmed to about room temperature, before cooling and addition to thealdehyde of formula (XId).

Compounds of formula (XId) may be prepared by conventional methods suchas those described in International (PCT) Patent Publication No. WO00/56727, for instance, by the oxidation of a corresponding vinylcompound using oxygen and ozone. The reaction is conveniently effectedat a reduced temperature, such as at about −78° C., in the presence ofan organic solvent such as an alcohol, for example, methanol, or ahalogenated hydrocarbon, for example, dichloromethane, or a mixturethereof. Treatment with dimethylsulfide liberates the desired aldehyde.

Compounds of formulae (IXd) where Q is —CH═ and (Xd) may be preparedfrom a compound of formula (XIId)

by reaction with a suitable Grignard reagent, for instance, of theformula CH₂═CHMgBr (for formula (IXd) where Q is —CH═) or CH₂═CHCH₂MgBr(for formula (Xd)). The reaction is effected in the presence of asuitable solvent such as an ether, for instance, diethyl ether ortetrahydrofuran, at a reduced temperature, for example, below −40° C.,and preferably at about −78° C. Cerium (III) chloride may be added toavoid reduction and enolization side reactions.

Compounds of formula (XIId) may be prepared from the correspondingcarboxylic acid by conventional procedures, for instance, by reaction ofthe carboxylic acid with (trimethylsilyl)diazomethane and methanol in asuitable solvent such as toluene, conveniently at room temperature.

Compounds of formula (IXd) where Q is —CH₂CH═ may be prepared from acompound of formula (XIIId)

by reaction with a suitable Grignard reagent, such as CH₂═CHMgBr orCH₂═CHMgCl, as previously described.

Compounds of formula (XIId) may be prepared from a compound of formula(XIVd)

by a suitable oxidation reaction, such as a Swern oxidation usingdimethylsulfoxide and oxalyl chloride, and a base such as triethylamine.The reaction is conveniently effected in a solvent such as a halogenatedhydrocarbon, for example, dichloromethane, at a reduced temperature, forexample at about −78° C., and then warming to room temperature.

Compounds of formula (XIVd) may be prepared from a compound of formula(XId) by reaction with a suitable Grignard reagent, such asCH₂═CHCH₂MgBr or CH₂═CHCH₂MgCl, as previously described.

According to a general process (Ae), compounds of formula (Ie) may beprepared by the reaction of a compound of formula (IIe)

with an amine of the formula R¹³R¹⁴NH,

The reaction is effected at an elevated temperature, for example,between 110° and 150° C., preferably at about 130° C., in a suitablesolvent, such as an alcohol, for instance, methanol.

Further details of suitable procedures will be found in the accompanyingExamples.

Compounds of formula (IIe) may be prepared from a compound of formula(IIIe)

by reaction with trimethylsulfonium iodide in the presence of a basesuch as sodium hydride. The reaction is conveniently effected in asuitable solvent such as dimethylsulfoxide or an ether, such astetrahydrofuran, or a mixture thereof, at a reduced temperature between−10° C. and +5° C., for example, at about 0° C.

Compounds of formula (IIIe) may be prepared by conventional methods suchas those described in International (PCT) Patent Publication No. WO00/56727, for instance, by the oxidation of a corresponding vinylcompound using oxygen and ozone. The reaction is conveniently effectedat a reduced temperature, such as at about −78° C., in the presence ofan organic solvent such as an alcohol, for example, methanol, or ahalogenated hydrocarbon, for example, dichloromethane, or a mixturethereof. Treatment with dimethylsulfide liberates the desired aldehyde.

Amines of use in the general process (Ae) are either known compounds, ormay be prepared by methods well known to one of ordinary skill in theart. For example, methods for the preparation of the spirocyclic aminesare provided in the literature—see for instance, Bioorg. Med. Chem.Lett., 12 (2002) 1759-62 and International (PCT) Patent Publication No.WO 01/87838.

According to a general process (Af), compounds of formula (If) whereinR¹¹ represents CO₂C₁-alkyl and R¹² represents OH, may be prepared by thetreatment of a compound of the formula (IIf)

with a lithiating agent such as an alkyl lithium compound, for example,sec-butyllithium in the presence of an organic base such asN,N,N′,N′-tetramethyl-1,2-ethanediamine, in a suitable solvent, such asan ether, for example, diethyl ether, at a reduced temperature, such asbelow −40°, and preferably at about −78° C.; which treatment is followedby reaction with a compound of formula (IIIf)

The reaction is conveniently effected in a suitable solvent, such as anether, for example, diethyl ether, at a reduced temperature, such asbelow −40°, and preferably at about −78° C.

According to another general process (Bf), compounds of formula (If)wherein R¹² is linked to R¹¹ such that there is formed a ring, thelinkage —R¹²—R¹¹— being —OC(O)—, may be prepared by the interconversionof a compound of formula (If) wherein R¹¹ represents CO₂C₁₋₆alkyl andR¹² represents OH by treatment with a reducing agent such as a hydride,for instance sodium hydride, the reaction being effected in a suitablesolvent such as an ether, for example, tetrahydrofuran, conveniently atabout room temperature.

According to another general process (Cf), compounds of formula (If)wherein R¹¹ represents hydrogen and R¹² represents OH (which compoundsmay themselves serve as precursors for further derivatization of theamino moiety, may be prepared by the interconversion of a compound offormula (If) wherein R¹² is linked to R¹¹ such that there is formed aring, the linkage —R¹²—R¹¹— being —OC(O)—, by treatment with lithiumhydroxide, the reaction being effected in a suitable solvent such as anether, for example, tetrahydrofuran, and alcohol, for example, methanol,or water, or a mixture thereof, at an elevated temperature, such asbetween 40° C. and 60° C., preferably at about 50° C.

Further details of suitable procedures will be found in the accompanyingExamples.

Compounds of formula (IIf) are either known compounds or they may beprepared by methods readily apparent to one of ordinary skill in theart.

Compounds of formula (IIIf) may be prepared by conventional methods suchas those described in International (PCT) Patent Publication No. WO00/56727, for instance, by the oxidation of a corresponding vinylcompound using oxygen and ozone. The reaction is conveniently effectedat a reduced temperature, such as at about −78° C., in the presence ofan organic solvent such as an alcohol, for example, methanol, or ahalogenated hydrocarbon, for example, dichloromethane, or a mixturethereof. Treatment with dimethylsulfide liberates the desired aldehyde.

It will be appreciated that the general methodology described above maybe adapted, using methods that are readily apparent to one of ordinaryskill in the art, in order to prepare further compounds of the presentinvention. In particular, compounds of formula (I) may be interconvertedinto further compounds of formula (I) using conventional synthetictechniques such as N-alkylation or O-alkylation, oxidation or reduction.

Thus, for instance, a compound of formula (Ia), (Iab) or (Ib) wherein Xis CHOH may be converted into a corresponding compound of formula (Ia),(Iab) or (Ib) respectively wherein X is C═O by reaction with a strongoxidizing agent, such as Dess-Martin periodinane, to afford the desiredketone.

Also, for instance, for the compounds of formula (Ic), the NR¹² moietywhere R¹² is hydrogen may be alkylated by reaction with a suitable alkylhalide, such as methyl iodide or ethyl iodide, conveniently at aboutroom temperature, in the presence of an acid acceptor such as potassiumcarbonate or N,N-diisopropylethylamine.

In another example of such interconversion reactions, the sulfur atom ofthe thiomorpholine ring of the compounds of formula (Ic) may be oxidizedusing, for instance, sodium metaperiodate in acetic acid to afford thecorresponding sulfoxide or sulfone.

Also, for instance, the compounds of formula (Id) having the NR¹¹ moietywhere R¹¹ is hydrogen and NH moieties in the compounds of formulae (Ie)and (If) may be alkylated by reaction with a suitable alkyl halide, suchas methyl iodide or ethyl iodide, conveniently at about roomtemperature, in the presence of an acid acceptor such as potassiumcarbonate or N,N-diisopropylethylamine.

In another example of such interconversion reactions, a compound offormula (Ie) or (If) wherein Z is S may be converted into acorresponding compound of formula (Ie) or (If) respectively wherein Z isSO or S(O)₂ by an oxidation reaction using, for instance, sodiummetaperiodate in acetic acid to afford the desired sulfoxide or sulfone.

Other general methods that may be adapted to the synthesis of the pyranacetal derivatives of the present invention are described inInternational (PCI) Patent Publication Nos. WO 00/56727 and WO 02/16344.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The exemplified compounds of this invention were tested by the methodsset out at pages 36 to 39 of International Patent Specification No. WO93/01165. The compounds were found to be active with IC₅₀ at the NK₁receptor of less than 100 nM on said test method.

The following non-limiting Examples serve to illustrate the preparationof compounds of the present invention:

Description 1 Piperidine-1,4-dicarboxylic acid 1-benzyl ester 4-ethylester

A solution of benzyl chloroformate (95 g, 0.56 mol) in dichloromethane(200 ml) was added dropwise to an ice-bath-cooled, stirred mixture ofethyl isonipecotate (87 g, 0.55 mol), sodium carbonate (60 g, 0.57 mol)and dichloromethane (200 ml) over 70 minutes. The mixture was stirred atambient temperature for 2.5 days and filtered though a pad of Celite™.The filtrate was concentrated in vacuo. The residue was partitionedbetween 2M aqueous hydrochloric acid and diethyl ether. Organic layerwas separated, dried (MgSO₄), filtered and concentrated. The residue waschromatographed on silica gel (ethyl acetate/iso-hexane) to give thetitle product (152 g, 94%).

¹H NMR (360 MHz, CDCl₃): δ 7.41-7.27 (5H, m), 5.12 (2H, s), 4.22-3.99(2H, m), 4.14 (2H, q, J 7.4 Hz), 2.93 (2H, br t, J 11.6 Hz), 2.45 (2H,m), 1.97-1.81 (2H, m), 1.74-1.56 (2H, m), 1.25 (3H, t, J 7.4 Hz).

Description 24-[2-(tert-Butyldimethylsilyloxy)-1-hydroxyethyl]-piperidine-1,4-dicarboxylicacid 1-benzyl ester 4-ethyl ester

A solution of piperidine-1,4-dicarboxylic acid 1-benzyl ester 4-ethylester (Description 1; 10 g, 34.4 mmol) in tetrahydrofuran (100 ml) wascooled to −78° C. Lithium bis(trimethylsilyl)amide (1.0M intetrahydrofuran, 50 ml, 50 mmol) was added dropwise and the mixturestirred, allowing to warm to room temperature over 1.5 hours. The orangesolution was re-cooled to −78° C. and(tert-butyldimethylsilyloxy)acetaldehyde (10 g, 57.3 mmol) added. Themixture was allowed to warm to room temperature over 2.5 hours, thenquenched with saturated aqueous ammonium chloride solution. The reactionmixture was partitioned between diethyl ether and water. The organiclayer was dried (MgSO₄) and concentrated in vacuo. The residue waspurified by flash column chromatography on silica, eluting with 5-15%diethyl ether/dichloromethane, to give the title compound (12.4 g, 78%).¹H NMR (400 MHz, CDCl₃): δ 7.36-7.35 (5H, m), 5.30 (2H, s), 4.21 (2H, q,J 7.1 Hz), 4.15-4.04 (2H, m), 3.66-3.57 (3H, m), 2.83 (2H, d, J 4.3 Hz),2.23-2.05 (2H, m), 1.63-1.56 (2H, m), 1.29 (3H, t, J 7.1 Hz), 0.88 (9H,s), 0.06 (6H, s).

Description 34-(1,2-Dihydroxyethyl)-4-hydroxymethyl-piperidine-1-carboxylic acidbenzyl ester

Lithium borohydride (1 g, 45 mmol) was added portionwise to a solutionof4-[2-(tert-butyldimethylsilyloxy)-1-hydroxyethyl]-piperidine-1,4-dicarboxylicacid 1-benzyl ester 4-ethyl ester (Description 2; 11.2 g, 24.1 mmol) intetrahydrofuran (75 ml). The mixture was stirred at room temperature for2 hours. The reaction was quenched by addition of saturated aqueoussodium hydrogencarbonate solution, then partitioned between ethylacetate and water. The organic layer was dried (MgSO₄) and concentratedin vacuo to give the diol. This was dissolved in tetrahydrofuran (50ml). Tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 32 ml, 32mmol) was added and the reaction stirred at room temperature for 1 hour.The mixture was partitioned between water and ethyl acetate. The organiclayer was dried (MgSO₄) and concentrated in vacuo. The residue waspurified by flash column chromatography on silica, eluting with 1, 2, 5and 10% methanol/ethyl acetate, to give the title compound (5.4 g, 73%).

¹H NMR (360 MHz, CDCl₃): δ 7.39-7.29 (5H, m), 5.13 (2H, s), 3.82-3.70(6H, m), 3.54 (1H, t, J 4.7 Hz), 3.26-2.74 (5H, m), 1.73-1.54 (3H, m),1.39-1.31 (1H, m).

Description 4 4-Hydroxy-2-oxa-8-aza-spiro[4.5]decane-8-carboxylic acidbenzyl ester

Diethyl azodicarboxylate (1.4 g, 8.1 mmol) was added to a solution of4-(1,2-dihydroxyethyl)-4-hydroxymethyl-piperidine-1-carboxylic acidbenzyl ester (Description 3; 2 g, 6.5 mmol) and triphenylphosphine (2.4g, 9.1 mmol) in tetrahydrofuran (40 ml). The reaction was stirred atroom temperature for 2 hours then the solvent was removed in vacuo. Theresidue was purified by flash column chromatography on silica, elutingwith 1, 2 and 4% methanol/dichloromethane, to give the title compound(1.43 g, 76%).

¹H NMR (400 MHz, CDCl₃): δ 7.38-7.30 (5H, m), 5.13 (2H, s), 4.12-4.08(1H, m), 4.02-3.99 (1H, m), 3.74-3.65 (5H, m), 3.39-3.33 (1H, m),3.27-3.20 (1H, m), 1.89-1.87 (1H, m), 1.82-1.76 (1H, m), 1.59-1.54 (1H,m), 1.51-1.48 (2H, m).

Description 54-[2-(tert-Butyldimethylsilyloxy)-1-hydroxyethyl]-piperidine-4-dicarboxylicacid 1-(1,1-dimethylethyl)ester 4-ethyl ester

The title compound was prepared as described in Description 2 frompiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester.

¹H NMR (360 MHz, CDCl₃): δ 4.21 (2H, q, J 7.0 Hz), 4.08-3.90 (2H, m),3.75-3.50 (3H, m), 2.89-2.69 (2H, m), 2.19 (1H, m), 2.03 (1H, m), 1.57(2H, dt, J 4.6, 13.0 Hz), 1.45 (9H, s), 1.29 (3H, t, J 7.4 Hz), 0.89(9H, s), 0.06 (6H, s).

Description 64-(1,2-Dihydroxyethyl)-4-hydroxymethyl-piperidine-1-carboxylic acid1,1-dimethylethyl ester

The title compound was prepared as described in Description 3 from theproduct of Description 5.

¹H NMR (400 MHz, CDCl₃): δ 3.80-3.60 (6H, m), 3.55 (1H, m), 3.24-3.02(3H, m), 1.73-1.48 (4H, m), 1.45 (9H, s), 1.33 (1H, m).

Description 7 4-Hydroxy-2-oxa-8-aza-spiro[4.5]decane-8-carboxylic acid1,1-dimethylethyl ester

The title compound was prepared as described in Description 4 from theproduct of Description 6.

¹H NMR (400 MHz, CDCl₃): δ 4.11 (1H, dd, J 4.7, 10.2 Hz), 4.01 (1H, dt,J 1.6, 4.7 Hz), 3.74 (1H, d, J 8.6 Hz), 3.73 (1H, dd, J 2.0, 10.7 Hz),3.67 (1H, d, J 8.6 Hz), 3.63 (2H, m), 3.27 (1H, dt, J 6.3, 13.7 Hz),3.14 (1H, ddd, J 3.5, 9.0, 12.9 Hz), 1.82 (1H, d, J 5.5 Hz), 1.77 (1H,ddd, J 3.9, 9.0, 13.3 Hz), 1.56 (1H, ddd, J 3.5, 6.3, 13.3 Hz),1.50-1.45 (2H, m), 1.46 (9H, s).

Description 8 (RS)-2-Oxa-8-aza-spiro[4.5]decan-4-ol hydrochloride

4-Hydroxy-2-oxa-8-aza-spiro[4.5]decane-8-carboxylic acid1,1-dimethylethyl ester (Description 7; 0.86 g, 3.3 mmol) was stirredovernight in 2M ethereal hydrogen chloride. The mixture was filtered andthe solid dried to give the title compound (0.5 g, 77%).

¹H NMR (360 MHz, MeOH-d₄): δ 4.15-4.06 (2H, m), 3.71-3.61 (3H, m),3.69-3.13 (4H, m), 2.08-2.03 (1H, m), 1.80-1.74 (3H, m).

Description 9(4R)-4-[(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carbonyloxy]-2-oxa-8-aza-spiro[4.5]decane-8-carboxylicacid benzyl ester and(4S)-4-[(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carbonyloxy]-2-oxa-8-aza-spiro[4.5]decane-8-carboxylicacid benzyl ester

(1S)-(−)-Camphanic chloride (335 mg, 1.54 mmol) was added to a stirredsolution of 4-hydroxy-2-oxa-8-aza-spiro[4.5]decane-8-carboxylic acidbenzyl ester (Description 4; 300 mg, 1.03 mmol), triethylamine (0.4 ml,2.9 mmol) and 4-N,N-dimethylaminopyridine (15 mg, 0.12 mmol) indichloromethane (5 ml). The mixture was stirred overnight and dilutedwith ethyl acetate and washed with saturated aqueous NaHCO₃, 2M HCl andwater. The organic phase was dried (Na₂SO₄) and concentrated. Theresidue was purified on silica (i-hexane:ethyl acetate) to give thetitle ester as a mixture of diastereoisomers (460 mg). Diastereoisomerswere separated on prep. HPLC (HIRPB, acetonitrile: 0.1% aq.trifluoroacetic acid) to give isomer A (190 mg) and isomer B (195 mg).

Isomer A: (4S)-Isomer of the Title Compound

¹H NMR (400 MHz, CDCl₃): δ 7.41 (5H, m), 5.13 (2H, s), 5.11 (1H, dd, J1.6, 4.7 Hz), 4.27 (1H, dd, J 4.7, 11.3 Hz), 3.87 (1H, d, J 8.6 Hz),3.77 (1H, dd, J 2.0, 11.3 Hz), 3.77-3.67 (2H, m), 3.67-3.58 (1H, m),3.40 (1H, dt, J 6.3, 14.1 Hz), 3.21 (1H, m), 2.38 (1H, ddd, J 4.3, 11.0,13.7 Hz), 2.05 (1H, dt, J 4.7, 9.4, 13.7 Hz), 1.94 (1H, ddd, J 4.3,10.6, 12.9 Hz), 1.77-1.67 (2H, m), 1.66-1.56 (3H, m), 1.12 (3H, s), 1.07(3H, s), 0.96 (3H, s).

Isomer B: (4R)-Isomer of the Title Compound

¹H NMR (400 MHz, CDCl₃): δ 7.40-7.29 (5H, m), 5.13 (2H, s), 5.11 (1H,dd, J 1.6, 4.7 Hz), 4.27 (1H, dd, J 5.1, 11.3 Hz), 3.87 (1H, d, J 8.6Hz), 3.77-3.66 (3H, m), 3.40 (1H, dt, J 6.3, 14.4 Hz), 3.21 (1H, m),2.43 (1H, ddd, J 4.3, 10.6, 13.3 Hz), 2.01 (1H, ddd, J 4.7, 9.0, 13.3Hz), 1.93 (1H, ddd, J 4.3, 10.6, 12.9 Hz), 1.80-1.65 (3H, m), 1.64-1.56(3H, m), 1.12 (3H, s), 1.04 (3H, s), 0.97 (3H, s).

Description 10(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylicacid (4R)-2-oxa-8-aza-spiro[4.5]dec-4-yl ester trifluoroacetate

A mixture of isomer B of the product of Description 9 (130 mg, 0.27mmol), palladium on carbon (10%, 73 mg), trifluoroacetic acid (0.1 ml)and ethanol (20 ml) was stirred at room temperature under H₂ atmosphere(balloon) for 30 minutes, and then filtered through a pad of Celite™ andconcentrated to give the title compound (130 mg).

¹H NMR (400 MHz, MeOH-d₄): δ 5.19 (1H, dd, J 2.0, 4.7 Hz), 4.29 (1H, dd,J 5.0, 10.8 Hz), 3.86 (1H, d, J 8.8 Hz), 3.76 (1H, dd, J 2.0, 11.1 Hz),3.69 (1H, d, J 8.8 Hz), 3.26-3.11 (3H, m), 3.03 (1H, ddd, J 3.5, 8.8,12.6 Hz), 2.50 (1H, ddd, J 6.1, 12.6, 15.2 Hz), 2.09-1.90 (3H, m),1.98-1.74 (3H, m), 1.63 (1H, m), 1.64-1.56 (3H, m), 1.10 (3H, s), 1.08(3H, s), 0.97 (3H, s).

Description 112-[1-{(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde

N-Methylmorpholine N-oxide (1 g, 8.6 mmol) and osmium tetroxide (2 ml,2.5% solution in tert-butanol) were added to a solution of(2R,3R,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-4-vinyl-tetrahydropyran(see Example 147 in WO 00/56727; 2 g, 4.3 mmol) in tetrahydrofuran (25ml) and water (10 ml). The mixture was stirred at room temperature forone hour before sodium periodate (9 g, 43 mmol) was added. This mixturewas stirred for 45 minutes and then filtered through Celite™. Thefiltrate was diluted with ethyl acetate (50 ml) and washed with brine.The organic extracts were dried and concentrated. The residue waschromatographed on silica gel eluting with ethyl acetate/iso-hexanes togive the title compound (1.6 g, 80%).

¹H NMR (400 MHz, CDCl₃): δ 9.47 (1H, s), 7.70 (1H, s), 7.27 (2H, s),7.15-7.12 (2H, m), 6.99-6.95 (2H, m), 4.97 (1H, q, J 6.6 Hz), 4.28-4.16(2H, m), 3.60-3.58 (1H, m), 3.00 (1H, dd, J 7.3, 10.6 Hz), 2.80-2.70(1H,m), 1.85-1.81 (2H, m), 1.39 (3H, d, J 6.6 Hz).

Description 12(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylicacid(4S)-8-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]dec-4-ylester

Palladium hydroxide (20% on carbon, 20 mg) was added as a slurry inethanol to a solution of isomer A of the product of Description 9 (120mg, 0.25 mmol) in ethanol (5 ml). The mixture was hydrogenated in a Parrapparatus (45 psi) for 30 minutes then filtered through Celite™ andwashed with ethanol. The filtrate was concentrated in vacuo. The residueand2-[1-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde(Description 11; 232 mg, 0.5 mmol) were suspended in 1,2-dichloroethane(10 ml) and stirred at room temperature for 30 minutes. Sodiumtriacetoxyborohydride (105 mg, 0.5 mmol) was added and the reactionstirred overnight at room temperature. The mixture was partitionedbetween dichloromethane and brine. The organic layer was dried (MgSO₄)and concentrated in vacuo. The residue was purified by preparative thinlayer chromatography, eluting with 7.5% methanol/dichloromethane, togive the title compound (138 mg, 70%).

m/z (ES+) 786 (M+H)⁺.

Description 13(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylicacid(4R)-8-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]dec-4-ylester

Solid sodium triacetoxyborohydride (107 mg, 0.504 mmol) was added to astirred mixture of2-[1-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde(Description 11; 121 mg, 0.36 mmol),(1S,4R)-4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylicacid (4R)-2-oxa-8-aza-spiro[4.5]dec-4-yl ester trifluoroacetate(Description 10; 130 mg), triethylamine (0.1 ml, 0.72 mmol) anddichloromethane (3 ml) at room temperature. The mixture was stirred for45 minutes, quenched with saturated aqueous NaHCO₃ and extracted intodichloromethane. The organic extract was dried (Na₂SO₄) andconcentrated. The residue was purified by preparative TLC(dichloromethane:methanol) to give the title compound (100 mg). The HClsalt was prepared and recrystallised from ethyl acetate:methanol.

¹H NMR (400 MHz, CDCl₃): δ 7.67 (1H, s), 7.17 (2H, s), 7.02-6.89 (4H,m), 4.98 (1H, m), 4.95 (1H, q, J 6.3 Hz), 4.23-4.08 (3H, m), 3.68 (1H,d, J 8.6 Hz), 3.66 (1H, dd, J 1.6, 9.4 Hz), 3.58-3.45 (2H, m), 2.50-2.33(3H, m), 2.25-1.83 (8H, m), 1.81-1.65 (2H, m), 1.57-1.40 (3H, m), 1.36(3H, d, J 6.6 Hz), 1.11 (3H, s), 1.02 (3H, s), 0.94 (3H, s); m/z (ES+)786 (M+H)⁺.

Description 14(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylicacid(4R)-8-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]dec-4-ylester (i)(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)tetrahydropyran-4-carbaldehydea) (3-Bromo-4-fluorophenyl)acetic acid 3-bromopropyl ester

(3-Bromofluorophenyl)acetyl chloride (30.2 g, 0.12 mol) was dissolved indichloromethane (70 mL) and the solution was cooled to 0° C.3-Bromopropanol (24.7 g, 0.177 mol) in dichloromethane (30 mL) was addeddropwise and the mixture was stirred at room temperature overnight. Themixture was washed with water, brine, dried MgSO₄) and the solvent wasremoved in vacuo. The resulting oil was purified on silica using 5-10%ethyl acetate in hexane to give the product (36 g, 82%).

¹H NMR (400 MHz, CDCl₃): δ 7.48 (1H, dd, J 2.3, 6.5 Hz), 7.19 (1H, ddd,J 2.3, 4.6, 8.5 Hz), 7.10 (1H, t, J 8.4 Hz), 4.25 (2H, t, J 6.1 Hz),3.58 (2H, s), 3.41 (2H, t, J 6.6 Hz), 2.17 (2H, quintet, J 6.2 Hz).

b) (3-Bromo-4-fluorophenyl)-3,4,5,6-tetrahydrohydropyran-2-one

Sodium hydride (4.62 g, 0.11 mol) was suspended in dimethylformamide(200 mL) and the suspension was warmed to 60° C. To this was addeddropwise (3-bromo-4-fluoro)phenylacetic acid 3-bromopropyl ester (fromstep a) above; 35.3 g) in dimethylformamide (20 mL) and the mixture wasstirred for 30 min until all gas evolution ceased. The mixture wascooled and quenched with water (10 mL) cautiously, and then diluted withwater (1500 mL) and extracted with ethyl acetate (3×100 mL). The pooledorganic extracts were washed with brine, dried (MgSO₄) and evaporated.The crude residue was purified by chromatography on silica using 10-30%ethyl acetate in hexane as eluant to give the lactone (17.1 g, 63%).

¹H NMR (400 MHz, CDCl₃): δ 7.44 (1H, dd, J 2.3, 6.2 Hz), 7.17 (1H, ddd,J 2.2, 4.6, 8.5 Hz), 7.07 (1H, t, J 8.4 Hz), 4.45 (2H, m), 3.72 (1H, dd,J 6.8, 10.2 Hz), 2.30 (1H, m), 2.03 (3H, m).

c) (±)3-Bromo-(3-bromo-4-fluorophenyl)-3,4,5,6-tetrahydrohydropyran-2-one

(3-Bromo-4-fluorophenyl)-3,4,5,6-tetrahydrohydropyran-2-one (from stepb) above; 14.82 g, 0.054 mol) was dissolved in carbon tetrachloride (200mL) and benzoyl peroxide (100 mg) and N-bromosuccinimide (11.63 g, 0.065mol) were added. The mixture was heated cautiously to reflux andmaintained at reflux for 3 h. The mixture was cooled, filtered andconcentrated. The crude residue was purified by chromatography on silicausing 10-100% ethyl acetate in hexane as eluant to give the bromide(17.9 g, 95%).

¹H NMR (400 MD, CDCl₃): δ 7.84 (1H, dd, J 2.6, 6.3 Hz), 7.57 (1H, ddd, J2.6, 4.4, 8.8 Hz), 7.13 (1H, t, J 8.6 Hz), 4.62 (1H, m), 4.42 (1H, m),2.80-2.60 (2H, m), 2.38 (1H, m), 2.30 (1H, m), 1.88 (1H, m).

d) 3-(3-Bromo-4-fluorophenyl)-5,6-dihydropyran-2-one

(±) 3-Bromo-(3-bromo-4-fluorophenyl)-3,4,5,6-tetrahydrohydropyran-2-one(from step c) above; 17.9 g, 0.051 mol) was dissolved in tetrahydrofuran(200 mL) and lithium bromide (6.6 g, 0.076 mol) and lithium carbonate(5.6 g, 0.076 mol) were added. The mixture was heated at reflux for 3 h,then cooled. The mixture was filtered to remove inorganic material. Thesolvent was removed in vacuo and the crude residue was purified bychromatography on silica using 10-50% ethyl acetate in hexane as eluantto give the enone (11.36 g, 82%).

¹H NMR (400 MHz, CDCl₃): δ 7.68 (1H, dd, J 2.8, 6.6 Hz), 7.41 (1H, ddd,J 2.2, 4.6, 8.6 Hz), 7.11 (1H, t, J 8.4 Hz), 7.00 (1H, t, J 4.6 Hz),4.49 (2H, t, J 6.3 Hz), 2.64 (2H, dt, J 4.6, 6.2 Hz).

e) (±)3-(3-Bromo-4-fluorophenyl)₄-vinyl-3,4,5,6-tetrahydrohydropyran-2-one

Copper iodide (375 mg, 5 mol %) was suspended in tetrahydrofuran (300mL) and the mixture was cooled to −78° C. To this mixture was addedvinylmagnesium chloride (25 mL, 1.7M) followed by dropwise addition of3-(3-bromo-4-fluorophenyl)-5,6-dihydropyran-2-one (from step d) above;10.64 g, 0.039 mol) and trimethylsilyl chloride (4.97 mL, 0.039 mol).The reaction progress was monitored by thin layer chromatography. Thereaction mixture was quenched by pouring, via double-ended needle, ontoammonium chloride (saturated aqueous solution). The mixture wasconcentrated in vacuo to remove tetrahydrofuran and the residue wasextracted with ethyl acetate (3×200 mL). The pooled organic extractswere washed with brine, dried (MgSO₄) and evaporated. The crude residuere-dissolved in tetrahydrofuran and 1,8-diazabicyclo[5.4.0]undec-7-ene(0.3 mL) was added. This solution was stirred for 4 h. Tetrahydrofuranwas removed in vacuo and the residue was purified by chromatography onsilica using 30-50% ethyl acetate in hexane as eluant to give the vinyllactone (11.5 g, 80%).

¹H NMR (400 MHz, CDCl₃): δ 7.37 (1H, d, J 6.6 Hz), 7.09 (2H, d, J 7.5Hz), 5.61 (1H, d, J 10.3 Hz), 4.92 (1H, d, 17.1 Hz), 4.57-4.43 (2H, m),3.44 (1H, d, J 10.9 Hz), 2.78 (1H, m), 2.16 (1H, m), 1.96 (1H, m).

f) (±) 3-(3-Bromo-4-fluorophenyl)-4-vinyltetrahydropyran-2-ol

(±) 3-(3-Bromofluorophenyl)-4-vinyl-3,4,5,6-tetrahydrohydropyran-2-one(from step e) above; 9.5 g, 0.032 mol) was dissolved in ethanol (90 mL)and cerium (M) chloride was added. The resulting solution was cooled to−30° C. and sodium borohydride (1.2 g, 0.032 mol) was added portionwise.The mixture was stirred for 30 min and was then quenched with acetone(188 mL). The solvent was removed in vacuo and the residue was dispersedbetween ethyl acetate and water. The mixture was filtered throughCelite™ to remove inorganic material. The combined organic extracts werewashed with brine and dried (MgSO₄). The solvent was removed in vacuo togive the lactol as a yellow solid (9.07 g, 94%).

¹H NMR (400 MHz, CDCl₃) 3:2 mixture: δ 7.48 (0.4H, m), 7.37 (0.6H, m),7.20-7.16 (0.4H, m), 7.12-7.00 (1.6H, m), 5.51-5.40 (1H, m), 5.16 (0.4H,s), 4.96-4.82 (2H, m), 4.73 (0.6H, dd, J 2.6, 8.1 Hz), 4.22-4.10 (1H,m), 3.75-3.67 (1H, m), 2.97 (0.4H, m), 2.84 (0.6H, m), 2.71 (0.4H, dd, J2.8, 11.8 Hz), 2.54-2.45 (0.6H, m), 2.40-2.32 (1H, m), 1.80-1.60 (2H,m).

g)(2R,3R,4S)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)-4-vinyltetrahydropyran

(±) 3-(3-Bromo-4-fluorophenyl)-4-vinyltetrahydropyran-2-ol (from step f)above; 10.32 g, 0.034 mol), (1R)-3,5-bis(trifluoromethyl)phenylethanol(11 g, 0.042 mol), Amberlyst™ (5 g) and molecular sieves (8 g) weresuspended in dichloromethane (20 mL) and the mixture was shaken at 40°C. for 3 days. The resulting yellow solution was filtered, concentratedin vacuo and was purified by chromatography on silica using 1-5% ethylacetate in hexane as eluant to give a mixture of isomers 1-3 (which wereretained) and the desired isomer 4 (3.6 g, 20%) as a colourless oil.

¹H NMR (400 MHz, CDCl₃): δ 7.69 (1H, s), 7.26-7.21 (3H, m), 6.98 (1H, tJ 8.4 Hz), 6.91 (1H, m), 5.43 (1H, ddd, J 7.1, 10.5, 17.4 Hz), 4.95 (1H,q, J 6.6 Hz), 4.83 (1H, d, J 10.6 Hz), 4.80 (1H, d, J 17.4 Hz), 4.16(1H, d, J 8.3 Hz), 4.14 (1H, m), 3.56 (1H, m), 2.49 (1H, dd, J 8.3, 11.6Hz), 2.38 (1H, m), 1.75-1.60 (2H, m), 1.40 (3H, d, J 6.6 Hz).

h)(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)tetrahydropyran-4-carbaldehyde

(2R,3R,4S)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)-4-vinyltetrahydropyran(from step g); 0.5 g, 0.924 mol) was dissolved in dichloromethane (10mL) and methanol (7 mL) and ozone was bubbled through the solution at−78° C. until a blue coloration persisted. The solution was purged withnitrogen and dimethyl sulfide (0.6 mL) was added dropwise. The mixturewas allowed to stir overnight. The solvent was removed in vacuo and theresidue was partitioned between ethyl acetate and water. The combinedorganic phase was dried (MgSO₄) and the solvent was evaporated. Theresidue was purified by chromatography on silica using 10-20% ethylacetate in hexane as eluant to afford the product aldehyde as acolourless oil (170 mg, 34%).

¹H NMR (CDCl₃): δ 1.42 (3H, d, J 6.6 Hz), 1.78-1.89 (2H, m), 2.68-2.74(1H, m), 3.01 (1H, dd, J 7.1, 10.3 Hz), 3.59-3.64 (1H, m), 4.10-4.19(1H, m), 4.28 (1H, d, J 7.1 Hz), 4.97 (1H, q, J 6.6 Hz), 7.03 (1H, t, J8.3 Hz), 7.08-7.11 (1H, m), 7.31 (2H, s), 7.39 (1H, dd, J 2.2, 6.6 Hz),7.72 (1H, s), 9.51 (1H, d, J 1.5 Hz).

(ii)(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylicacid(4R)-8-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]dec-4-ylester

(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylicacid (4R)-8-aza-8-benzyloxycarbonyl-2-oxa-spiro[4.5]dec-4-yl ester(Description 9, isomer B; 100 mg, 0.21 mmol) was dissolved in methanol(20 ml) and trifluoroacetic acid (0.1 ml) and Pd (10% on carbon, 20 mg)were added under nitrogen. The mixture was purged with hydrogen gas andstirred for 30 min under a balloon of hydrogen. The mixture was purgedwith nitrogen and filtered to remove catalyst; solvents were removed invacuo to give the amine as a colourless oil.

m/z 338 (M⁺+1, 100%).

The amine salt was dissolved in dichloroethane (3 ml) and triethylamine(0.056 ml, 0.4 mmol) followed by(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)tetrahydropyran-4-carbaldehyde(Description 14(i); 130 mg, 0.25 mmol) and sodium triacetoxyborohydride(63 mg, 0.318 mmol) and the resulting mixture was stirred for 30 min.The mixture was then diluted with dichloromethane and washed with sodiumbicarbonate (saturated aqueous solution). The organic extracts werepooled, washed with brine, dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by chromatography on silica gel using 1-5% methanolin dichloromethane as eluant. This afforded the product as a white solid(150 mg, 83%).

This was further purified by recrystallisation of the HCl salt fromether-ethyl acetate to give the product as white crystals (140 mg).

¹H NMR (500 MHz, CDCl₃): δ 7.69 (1H, s), 7.22 (1H, dd overlapped, J 2.0Hz), 7.21 (3H, s), 6.98 (1H, t, J 8.3 Hz), 6.92-6.89 (1H, m), 5.00 (1H,dd, J 1.3, 4.5 Hz), 4.95 (1H, q, J 6.6 Hz), 4.18 (1H, dd, J 11.5, 4.7Hz), 4.17-4.13 (1H, m), 4.10 (1H, d, J 8.3 Hz), 3.72 (1H, d, J 8.3 Hz),3.66 (1H, d, J 11.0 Hz), 3.54 (1H, d, J 8.5 Hz), 3.50 (1H, br d),2.43-2.33 (3H, m), 2.17-2.11 (1H, m), 2.07-1.83 (9H, m), 1.72-1.62 (2H,m), 1.50-1.38 (3H, m), 1.38 (3H, d, J 6.6 Hz), 1.11 (3H, s), 1.02 (3H,s), 0.94 (3H, s); m/z (ES+) 864 (M+1, 100%), 866 (M⁺+1, 95%).

Description 15[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methanol

Sodium borohydride (24 mg, 0.63 mmol) was added to solution of2-[1-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-carbaldehyde(see Example 2 in WO 02/16344; 107 mg, 0.23 mmol) in methanol (3 ml).The mixture was stirred for 30 minutes then quenched with saturatedaqueous NaHCO₃ and extracted into ethyl acetate. The combined organicextracts were dried and concentrated to give the title compound (104mg).

¹H NMR (360 MHz, CDCl₃): δ 7.70 (1H, s), 7.21 (2H, s), 7.05 (1H, m),6.97 (1H, ddd, J 1.8, 7.4, 10.9 Hz), 6.79 (1H, m), 4.97 (1H, q, J 6.7Hz), 4.22-4.11 (2H, m), 3.55 (1H, dt, J 2.5, 12.3 Hz), 3.39 (1H, m),3.24 (1H, m), 2.57 (1H, dd, J 8.4, 11.2 Hz), 1.94-1.78 (2H, m), 1.68(1H, m), 1.39 (3H, d, J 6.7 Hz), 1.18 (1H, m).

Description 16 Methanesulfonic acid[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)-phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methylester

Methanesulfonyl chloride (50 μl, 0.63 mmol) was added to a mixture of[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methanol(Description 15; 235 mg, 0.49 mmol), triethylamine (133 ml, 0.97 mmol),4-N,N-dimethylaminopyridine (3 mg, 0.02 mmol) and dichloromethane (5 ml)at 0° C. The mixture was stirred for 30 minutes, then quenched withsaturated aqueous NaHCO₃ and extracted into dichloromethane. Thecombined organic extracts were dried and concentrated. The product wasused in the next step without further purification.

¹H NMR (400 MHz, CDCl₃): δ 7.70 (1H, s), 7.20 (2H, s), 7.09 (1H, dt, J8.6, 9.8 Hz), 6.88 (1H, ddd, J 2.0, 7.4, 11.0 Hz), 6.81 (1H, m), 4.97(1H, q, J 6.7 Hz), 4.21-4.12 (2H, m), 3.95 (1H, dd, J 3.1, 9.8 Hz), 3.80(1H, dd, J 7.4, 10.2 Hz), 3.55 (2H, dt, J 2.4, 12.1 Hz), 2.90 (3H, s),2.58 (1H, dd, J 8.2, 11.7 Hz), 2.12 (1H, m), 1.86 (1H, m), 1.78-1.66(1H, m), 1.39 (3H, d, J 6.7 Hz).

Description 17 1-Oxa-8-azaspiro[4.5]decane Hydrochloride (i)1,1-Dimethylethyl4-hydroxy-4-(3-trimethylsilyloxypropynyl)-1-piperidinecarboxylate

Trimethyl(2-propynyloxy)silane (11.54 ml, 9.62 g, 75 mmol) was addeddropwise to a stirred, cooled (−5° C.) solution of ethyl magnesiumbromide (1M in tetrahydrofuran, 75 ml, 75 mmol) in tetrahydrofuran (150ml), maintaining the internal temperature below 0° C. The mixture wasstirred at 0° C. for 30 minutes, then at room temperature for 90minutes. The mixture was cooled to −5° C. and 1,1-dimethylethyl4-oxo-1-piperidinecarboxylate (15.0 g, 75 mmol) was added slowly,maintaining the internal temperature below 0° C. The mixture was stirredat 0° C. for 3 hours then at room temperature for 96 hours. Saturatedaqueous ammonium chloride (300 ml), water (100 ml) and ethyl acetate(300 ml) were added and the layers were separated. The aqueous layer wasextracted with ethyl acetate (200 ml) and the combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reduced pressureto give the title compound (24.4 g, 100%).

¹H NMR (400 MHz, CDCl₃): δ 4.36 (2H, s), 3.80-3.70 (2H, m), 3.35-3.25(2H, m), 1.95-1.85 (2H, m), 1.78-1.60 (3H, m), 1.48 (9H, s), 0.2 (9H,s).

(ii) 1,1-Dimethylethyl4-hydroxy-4-(3-hydroxypropynyl)-1-piperidinecarboxylate

Tetrabutylammonium fluoride (1M in tetrahydrofuran, 80 ml, 80 mmol) wasadded to a solution of 1,1-dimethylethyl4-hydroxy-4-(3-trimethylsilyloxypropynyl)-1-piperidinecarboxylate (fromstep (i) above; 24.4 g, 75 mmol) in tetrahydrofuran (300 ml) and themixture was stirred at room temperature for 18 hours. The solvent wasevaporated under reduced pressure and water (200 ml) was added. Themixture was extracted with ethyl acetate (2×200 ml) and the combinedorganic fractions were washed with water (2×200 ml) and brine (200 ml),dried (MgSO₄) and the solvent was evaporated under reduced pressure togive the title compound as an orange oil (16.8 g, 88%).

¹H NMR (400 MHz, CDCl₃): δ 4.32 (2H, s), 3.80-3.68 (2H, m), 3.32-3.22(2H, m), 1.93-1.83 (2H, m), 1.75-1.65 (2H, m), 1.62 (1H, br s), 1.46(9H, s).

(iii) 1,1-Dimethylethyl4-hydroxy-4-(3-hydroxypropyl)-1-piperidinecarboxylate

Palladium on carbon (5%, 800 mg) was added to a solution of1,1-dimethylethyl4-hydroxy-4-(3-hydroxypropynyl)-1-piperidinecarboxylate (from step (ii)above; 8.37 g, 32.8 mmol) in ethanol (400 ml), acetic acid (40 ml) andwater (5 ml) and the mixture was shaken under an atmosphere of hydrogen(40 psi) for 20 hours. The mixture was filtered through Hyflo™ and thesolvent was evaporated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel, eluting withisohexane/EtOAc (50:50 increasing to 0:100), to give the title compound(4.84 g, 57%).

¹H NMR (400 M&, CDCl₃): δ 3.85-3.75 (2H, m), 3.70 (2H, t, J 6 Hz), 3.18(2H, br t, J 14 Hz), 2.00 (2H, br s), 1.73-1.65 (2H, m), 1.63-1.48 (6H,m), 1.46 (9H, s).

(iv) 1,1-Dimethylethyl 1-oxa-3-azaspiro[4.5]decane-8-carboxylate

A solution of diethyl azodicarboxylate (3.35 ml, 21.3 mmol) intetrahydrofuran (50 ml) was added over 15 minutes to a stirred, cooled(0° C.) solution of 1,1-dimethylethyl4-hydroxy-4-(3-hydroxypropyl)-1-piperidinecarboxylate (from step (iii)above; 4.6 g, 17.8 mmol) and triphenylphosphine (5.58 g, 21.3 mmol) intetrahydrofuran (150 ml) and the mixture was stirred at 0° C. for 1hour, then at room temperature for 24 hours. The solvent was evaporatedunder reduced pressure and the residue was purified by flash columnchromatography on silica gel, eluting with isohexane/EtOAc (75:25increasing to 50:50), to give the title compound (3.18 g, 70%).

¹H NMR (400 MHz, CDCl₃): δ 3.83 (2H, t, J 7 Hz), 3.63-3.53 (2H, m),3.38-3.28 (2H, m), 1.93 (2H, quin., J 7 Hz), 1.69 (2H, t, J 7 Hz),1.63-1.48 (4H, m), 1.46 (9H, s); m/z (ES⁺) 242 (M+1).

(v) 1-Oxa-8-azaspiro[4.5]decane Hydrochloride

Methanolic hydrogen chloride (3M, 20 ml) was added over 10 minutes to astirred, cooled (0° C.) solution of 1,1-dimethylethyl1-oxa-8-azaspiro[4.5]decane-8-carboxylate (from step (iv) above, 3.18 g,13.2 mmol) in methanol (10 ml) and the mixture was stirred at roomtemperature for 3 hours. The solvent was evaporated under reducedpressure to give the title compound (2.29 g, 98%).

¹H NMR (400 MHz, CDCl₃): δ 3.85 (2H, t, J 7 Hz), 3.27-3.15 (4H, m), 1.98(2H, quin., J 7 Hz), 1.86-1.75 (6H, m); m/z (ES⁺) 142 (M+1).

Description 18 2,2-Dimethyl-1-oxa-8-azaspiro[4.5]decane (i)1,1-Dimethylethyl4-(3-ethoxy-3-oxo-1-propynyl)-4-hydroxy-1-piperidinecarboxylate

n-Butyllithium (175 ml, 0.28 mol) was added dropwise over 45 minutes toa stirred, cooled (−70° C.) solution of ethyl propiolate (32 ml, 0.32mol) in tetrahydrofuran (250 ml). The mixture was stirred at −70° C. for10 minutes, then a solution of 1,1-dimethylethyl4-oxo-1-piperidinecarboxylate (18.6 g, 0.093 mol) in tetrahydrofuran(250 ml) was added dropwise over 1 hour maintaining the internaltemperature below −70° C. The mixture was stirred at −70° C. for 1 hourand then acetic acid (21 ml) in tetrahydrofuran (50 ml) was added. Themixture was warmed to room temperature and the solvent was evaporatedunder reduced pressure. Saturated aqueous sodium hydrogen carbonate (300ml) and ethyl acetate (650 ml) were added and the layers were separated.The aqueous fraction was extracted with ethyl acetate (2×650 ml) and thecombined organic fractions were washed with brine, dried (Na₂SO₄) andthe solvent was evaporated under reduced pressure. The residue waspurified by chromatography on a short silica gel column, eluting with1:1 isohexane:ethyl acetate, to give the title compound (29.2 g,contains trace impurity).

¹H NMR (400 MHz, CDCl₃): δ 4.24 (2H, q, J 7 Hz), 3.73-3.68 (2H, m),3.38-3.31 (2H, m), 1.98-1.91 (2H, m), 1.80-1.72 (2H, m), 1.46 (9H, s),1.31 (3H, t, J 71H); m/z (ES⁺) 298 (M+1).

(ii) 1,1-Dimethylethyl4-(3-ethoxy-3-oxoprop-1-yl)-4-hydroxy-1-piperidinecarboxylate

Palladium on carbon (5%, 1 g) in water (10 ml) was added to a solutionof 1,1-dimethylethyl4-(3-ethoxy-3-oxo-1-propynyl)-4-hydroxy-1-piperidinecarboxylate (fromstep (i) above; 14.6 g, 0.046 mol) in ethanol (200 ml) and the mixturewas shaken under hydrogen (45 psi) for 90 minutes. The mixture wasfiltered through a glass fibre pad and the solvent was evaporated underreduced pressure to give the title compound.

¹H NMR (400 MHz, CDCl₃) δ 4.14 (21H, q, J 7 Hz), 3.80 (2H, br s),3.20-3.11 (2H, m), 2.45 (2H, t, J 7 Hz), 1.81 (2H, t, J 7 Hz), 1.58-1.42(4H, m), 1.45 (9H, s), 1.26 (3H, t, J 7 Hz); m/z (ES⁺) 302 (M+1).

(iii) 1,1-Dimethylethyl 1-oxa-2-oxo-8-azaspiro[4.5]decane-8-carboxylate

p-Toluenesulfonic acid (1.75 g, 9.2 mmol) was added to a solution of1,1-dimethylethyl4-(3-ethoxy-3-oxoprop-1-yl)-4-hydroxy-1-piperidinecarboxylate (from step(ii) above; 27.63 g, 0.092 mol) in toluene (250 ml) and the mixture washeated under reflux for 3 hours. The mixture was cooled and the solventwas evaporated under reduced pressure. Water (400 ml) and ethyl acetate(400 ml) were added and the layers were separated. The aqueous fractionwas extracted with ethyl acetate (200 ml). The combined organicfractions were washed with brine, dried (MgSO₄) and the solvent wasevaporated under reduced pressure to give the title compound (20.86 g,88%).

¹H NMR (400 MHz, CDCl₃): δ 3.84-3.79 (2H, m), 3.26 (2H, br t), 2.62 (2H,t, J 7 Hz), 2.05 (2H, t, J 7 Hz), 1.83-1.79 (2H, m), 1.68-1.62 (2H, m),1.46 (9H, s); m/z (ES⁺) 256 (M+1).

(iv) 1,1-Dimethylethyl4-hydroxy-4-(3-hydroxy-3-methylbut-1-yl)-1-piperidinecarboxylate

1,1-Dimethylethyl 1-oxa-2-oxo-8-azaspiro[4.5]decane-8-carboxylate (fromstep (iii) above; 5.0 g, 19.58 mmol) in tetrahydrofuran (150 m]) wasadded dropwise over 45 min. to a stirred, cooled (0° C.) solution ofmethyl magnesium chloride (3M in tetrahydrofuran, 19.58 ml, 58.75 mmol)in tetrahydrofuran (150 ml). The mixture was allowed to warm to roomtemperature and stirred overnight. The mixture was poured into saturatedaqueous ammonium chloride (200 ml) and extracted with ethyl acetate (200ml). The organic fraction was washed with brine, dried (Na₂SO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel, eluting with ethylacetate, to give the title compound (3.9 g, 69%).

¹H NMR (400 MHz, CDCl₃): δ 3.85-3.75 (2H, m), 3.20-3.10 (2H, m),2.55-2.25 (2H, m), 1.58-1.45 (6H, m), 1.46 (9H, s), 1.24 (6H, s); m/z(ES⁺) 214 (M+1-C₄H₈—H₂O).

(v) 2,2-Dimethyl-1-oxa-8-azaspiro[4.5]decane

Trifluoroacetic acid (10 ml) was added to a solution of1,1-dimethylethyl4-hydroxy-4-(3-hydroxy-3-methylbut-1-yl)-1-piperidinecarboxylate (fromstep (iv) above; 3.9 g, 13.57 mmol) in dichloromethane (10 ml) and themixture was stirred at room temperature overnight. The solvent wasevaporated under reduced pressure and the residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(90:10:1) to give the title compound (2.04 g, 89%).

¹H NMR (400 MHz, CDCl₃): δ 3.27-3.17 (4H, m), 1.95-1.82 (6H, m), 1.70(2H, d, J 13.4 Hz), 1.22 (6H, s); m/z (ES⁺) 170 (M+1).

Description 19 6-Oxa-2-azaspiro[3.4]octan-8-ol (i)1-Benzyloxycarbonyl-3-azetidinecarboxylic acid

3-Azetidinecarboxylic acid (4.0 g, 39.6 mmol) was dissolved in 1N sodiumhydroxide solution (40 mL) and cooled to 0° C. Benzyl chloroformate (5.9mL, 41 mmol) was added followed by further 1N sodium hydroxide solution(41 mL) dropwise. The mixture was stirred vigorously for 16 hrs thenmade acidic with 2N hydrochloric acid. This suspension was extractedwith dichloromethane (2×100 mL) and the extracts dried over MgSO₄.Concentration yielded the title compound (9.3 g, 39.6 mmol, 100%).

¹H NMR (400 MHz, CDCl₃): δ 7.37-7.29 (5H, m), 5.10 (2H, s), 4.21 (4H, d,J 7.5 Hz), 3.43 (1H, quintet, J 7.5 Hz).

(ii) Methyl 1-benzyloxycarbonyl-3-azetidinecarboxylate

1-Benzyloxycarbonyl-3-azetidinecarboxylic acid (from step (i); 9.3 g,39.6 mmol) was dissolved in methanol (100 mL) and toluene (100 mL), andcooled to 0° C. A solution of 2M trimethylsilyldiazomethane in hexaneswas then added dropwise until bubbling had ceased and the yellow colourpersisted. Acetic acid was then added dropwise until the yellow colourdisappeared. Concentration of the solution yielded the title compound asan oil (9.48 g, 38 mmol, 96%).

¹H NMR (400 MHz, CDCl₃): δ 7.36-7.31 (5H, m), 5.10 (2H, s), 4.19 (4H, d,J 7.8 Hz), 3.75 (3H, s), 3.39 (1H, quintet, J 7.8 Hz).

(iii) Benzyl3-(1,2-dihydroxyethyl)-3-(hydroxymethyl)azetidine-1-carboxylate

Methyl 1-benzyloxycarbonyl-3-azetidinecarboxylate (from step (ii); 10.1g, 40 mmol) was dissolved in tetrahydrofuran (120 mL) and cooled to −78°C. A solution of lithium hexamethyldisilazide in tetrahydrofuran (1M, 58mL, 58 mmol) was slowly added and the solution warmed to 0° C. After 15mins. at this temperature, the resulting solution was cooled back to−78° C. and tert-butyldimethylsilyloxy acetaldehyde was added andstirred to room temperature over 2 hrs and quenched with water (200 mL).This suspension was extracted with ethyl acetate (2×200 mL). Theextracts were dried (MgSO₄) and concentrated. The residue was flushedthrough silica with 25% ethyl acetate in hexanes to give a 1:2 mixtureof 1-benzyl 3-methyl3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-hydroxyethyl)azetidine-1,3-dicarboxylate:starting material (4.24 g).

This mixture was dissolved in tetrahydrofuran (30 mL) and treated withlithium borohydride (395 mg, 18 mmol). After 2 hrs at room temperature,the mixture was quenched with 1N sodium hydroxide solution (100 mL) andextracted with ethyl acetate (2×100 mL). The extracts were dried (MgSO₄)and concentrated to give crude benzyl3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-hydroxyethyl)-3-(hydroxylmethyl)azetidine-1-carboxylate. This was dissolved in tetrahydrofuran (100 mL)and treated with 1M tetra-n-butylammonium fluoride in tetrahydrofuran(10 mL, 10 mmol). After stirring for 1 hr at room temperature, water(200 mL) was added and the mixture extracted with ethyl acetate (2×200mL). The combined extracts were dried (MgSO₄) and concentrated. Theresidue was purified by silica chromatography to give the title compoundas an oil (956 mg, 3.4 mmol).

¹H NMR (400 MHz, CDCl₃): δ 7.37-7.29 (5H, m), 5.09 (2H, s), 3.96-3.64(9H, m), 3.13 (2H, br m), 1.69 (1H, br m).

(iv) Benzyl 8-hydroxy-6-oxa-2-azaspiro[3.4]octane-2-carboxylate

Benzyl 3-(1,2-dihydroxyethyl)-3-(hydroxymethyl)azetidine-1-carboxylate(from step (iii); 956 mg, 3.4 mmol) was dissolved in dichloromethane(150 mL) and dibutyltin oxide (17 mg) was added. p-Toluenesulfonylchloride (686 mg, 3.6 mmol) was added and the solution was cooled to 0°C. Triethylamine (520 μL, 3.75 mmol) was added dropwise and the solutionwas then allowed to stir at ambient temperature for 16 hrs. Furthertriethylamine (260 μL, 1.9 mmol) was added and after stirring for 2 hrs,water (250 mL) was added. The mixture was extracted with dichloromethane(2×250 mL), and the extracts dried (MgSO₄) then concentrated. Theresidue was purified by silica chromatography to give the title compoundas an oil (456 mg, 1.7 mmol, 51%).

¹H NMR (400 MHz, CDCl₃): δ 7.37-7.29 (5H, m), 5.10 (2H, s), 4.31-4.27(2H, m), 3.97 (2H, dd, J 9.1, 24 Hz), 3.94-3.91 (1H, m), 3.86 (1H, d, J9.5 Hz), 3.85 (2H, dd, J 9.1, 20 Hz), 3.74 (1H, dd, J 1.9, 10.2 Hz),1.95 (1H, d, J 4.4 Hz).

(v) 6-Oxa-2-azaspiro[3.4]octan-3-ol

Benzyl 8-hydroxy-6-oxa-2-azaspiro[3.4]octane-2-carboxylate (from step(iv); 456 mg, 1.7 mmol) was dissolved in methanol (20 mL) and 10%palladium on carbon (50 mg) added. This suspension was hydrogenated at20 psi hydrogen for 2 hrs then filtered. The filtrate was concentratedto give the title compound as a gum (214 mg, 1.66 mmol, 98% yield).

m/z (ES⁺) 130 (M+H).

Description 20 4-Hydroxy-1-oxa-8-azaspiro[4.5]decane (i) tert-Butyl4-(3-{[tert-butyl(dimethyl)silyl]oxy}propylidene)piperidine-1-carboxylate

3-{[tert-Butyl(dimethyl)silyl]oxy}propyl)(triphenyl)phosphonium bromide(J. Med Chem 1990, 33, 1958) (5.15 g, 0.01 mol) was suspended in tolueneand azeotroped to remove any moisture. It was then suspended in1,2-dimethoxyethane (20 mL) and n-butyllithium (7.0 mL, 1.6M. 0.011 mol)was added dropwise until a yellow coloration persisted. tert-Butyl4-oxopiperidine-1-carboxylate (2 g, 0.01 mol) was added and the mixturewas heated at reflux overnight. The cooled mixture was diluted withwater and extracted with ethyl acetate (2×50 mL), dried (MgSO₄) andconcentrated in vacuo. The crude yellow oil was purified on silica using10-30% ethyl acetate in iso-hexane as eluant.

¹H NMR (500 MHz, CDCl₃): δ 0.01 (6H, s), 0.84 (9H, s), 2.06-2.18 (4H,m), 2.20 (2H, t, J 7.0 Hz), 3.33 (4H, multiplet centre (mc)), 3.53 (2H,t, J 7.0 Hz), 5.24 (1H, t, J 7.2 Hz); m/z (ES⁺) 256 (M⁺+1-100, 100%).

(ii) tert-Butyl4-(1,3-dihydroxypropyl)-4-hydroxypiperidine-1-carboxylate

tert-Butyl4-(3-{[tert-butyl(dimethyl)silyl]oxy}propylidene)piperidine-1-carboxylate(from step (i) above; 0.9 g) was dissolved in tetrahydrofuran (1 mL);tetra-n-butylammonium fluoride (2.5 mL, 1M in THF) was added and themixture was stirred for 30 min until tlc analysis (50:50 ethylacetate:hexane) showed that all starting material had reacted. Thismixture was concentrated in vacuo. The crude product was re-dissolved intert-butanol (5 mL) and water (1 mL) and N-methylmorpholine N-oxide (322mg) was added and stirred until dissolved. Osmium tetroxide (0.15 mL,2.5% in t-butanol) was added and the mixture was stirred for 12 h. Thismixture was concentrated in vacuo. The crude product was purified bychromatography on silica using 1-6% methanol in dichloromethane aseluant to afford the product (480 mg).

¹H NMR (500 MHz, CDCl₃): δ 1.45 (9H, s), 1.40-1.85 (6H, m), 3.02-3.15(2H, m), 3.60 (1H, dd, J 12, 4 Hz), 3.85-4.00 (4H, m); m/z (ES⁺) 176(M⁺+1-100, 100%).

(iii) tert-Butyl 4-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

tert-Butyl 4-(1,3-dihydroxypropyl)-4-hydroxypiperidine-1-carboxylate(from step (ii) above; 480 mg) was dissolved in dichloromethane andp-toluenesulfonyl chloride was added followed by triethylamine (0.49 mL)and the mixture was stirred for 12 h. An additional aliquot oftriethylamine was added (0.49 mL) and the mixture stirred for 48 h. Thismixture was concentrated in vacuo. The crude product was purified bychromatography on silica using 50-95% ethyl acetate in iso-hexane aseluant to afford the product (300 mg).

¹H NMR (500 MHz, CDCl₃): δ 1.45 (9H, s), 1.48-1.67 (2H, br m), 1.95 (1H,mc), 2.32 (1H, mc), 3.18 (2H, mc), 3.72-3.83 (1H, br m), 3.85 (2H, mc),3.99 (2H, mc); m/z (ES⁺) 158 (M⁺+1-100, 100%).

(iv) 4-Hydroxy-1-oxa-8-azaspiro[4.5]decane trifluoroacetate

tert-Butyl 4-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (fromstep (iii) above; 300 mg) was dissolved in dichloromethane andtrifluoroacetic acid (2 mL) was added. The solution was stirred for 2 hand was concentrated in vacuo to afford the product as a colorless oil.

¹H NMR (500 MHz, CDCl₃): δ 1.61-1.66 (1H, m), 1.89-2.06 (3H, m),2.27-2.31 (2H, m), 3.20-3.33 (3H, m), 3.35-3.42 (1H, m), 3.85 (1H, mc),3.99 (1H, q, J 8.5 Hz), 4.07 (1H, dd, J 6.5, 4.0 Hz); m/z (s+) 158 (M⁺1,100%).

Description 21 4-Hydroxy-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane (i)Benzyl4-(acetyloxy)-3,3-dimethyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-3-carboxylate

A solution of 1-benzyl 4-ethyl piperidine-1,4-dicarboxylate (2.35 g) wasdissolved in tetrahydrofuran (30 mL) and was cooled to −78° C. Lithiumbis(trimethylsilyl)amide (9 mL, 1M) was added dropwise under nitrogenand the solution was stirred for 30 min at −20° C. The solution wasre-cooled to −78° C. and 1,1-dimethyl-2-oxoethyl acetate (1.17 g) intetrahydrofuran (5 mL) was added and the mixture was stirred for 30 min.The mixture was quenched (NaHCO₃, 30 mL) and the mixture was extractedwith ethyl acetate (2×50 mL). The extracts were combined, washed withbrine, dried (MgSO₄) and were concentrated in vacuo. The crude productwas purified by chromatography on silica using 25-75% ethyl acetate iniso-hexane as eluant to afford the product (1.4 g).

m/z (ES⁺) 376 (M⁺+1, 100%).

(ii) Benzyl4-(1,2-dihydroxy-2-methylpropyl)-4-(hydroxymethyl)piperidine-1-carboxylate

Benzyl4-(acetyloxy)-3,3-dimethyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate(from step (i) above; 1.4 g) was dissolved in tetrahydrofuran andlithium borohydride (81 mg) was added. The mixture was heated underreflux for 2 h, cooled and quenched carefully with water and HCl (30 mL,5N). The mixture was extracted with ethyl acetate and dried (MgSO₄), andconcentrated in vacuo. The crude product was purified by chromatographyon silica using 2-5% methanol in dichloromethane as eluant to afford theproduct (340 mg).

m/z (ES⁺) 338 (M⁺+1, 80%) 320 (M⁺+1-18, 100%).

(iii) Benzyl4-hydroxy-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

Benzyl4-(1,2-dihydroxy-2-methylpropyl)-4-(hydroxymethyl)piperidine-1-carboxylate(from step (iii) above; 340 mg) was dissolved in dichloromethane andp-toluenesulfonyl chloride (190 mg) was added, followed by triethylamine(0.14 mL). This mixture was stirred for 2 h and a second aliquot oftriethylamine was added and the mixture was stirred for 12 h. Themixture was concentrated in vacuo. The crude product was purified bychromatography on silica using 50-100% ethyl acetate in iso-hexane aseluant to afford the product (190 mg).

¹H NMR (500 MHz, CDCl₃): δ 1.18 (3H, s), 1.29 (3H, s), 1.46-1.59 (2H,m), 1.62-1.78 (2H, m), 3.00-3.13 (2H, m), 3.55 (1H, d, J 9.3 Hz), 3.73(1H, d, J 9.3 Hz), 3.84-3.95 (2H, m), 5.12 (2H, s), 7.29-7.36 (5H, m);m/z (ES⁺) 320 (M⁺+1, 100%).

(iv) 4-Hydroxy-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane

Benzyl 4-hydroxy-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate(from step (iii) above; 180 mg) was dissolved in methanol and palladiumon carbon (5%) was added. The mixture was hydrogenated at atmosphericpressure for 30 min. The catalyst was removed by filtration throughHyflo™ and the solvent was evaporated in vacuo to afford the product asa white solid.

¹H NMR (500 MHz, CDCl₃): δ 1.13 (3H, s), 1.24 (3H, s), 1.45-1.50 (2H,m), 1.67-1.79 (2H, m), 2.64-2.71 (2H, m), 2.89-3.00 (2H, m), 3.47 (1H,s), 3.59 (1H, d, J 9.2 Hz), 3.72 (1H, d, J 9.2 Hz); m/z (ES⁺) 186 (M⁺+1,100%).

Description 22 1-Oxa-8-aza[4.5]decan-3-ol (i) tert-Butyl4-hydroxy-4-{3-[(trimethylsilyl)oxy]prop-1-yn-1-yl}piperidine-1-carboxylate

Ethyl magnesium bromide in tetrahydrofuran (55 mL, 1M, 55 mmol) wasslowly added to a solution of trimethyl(prop-2-yn-1-yloxy)silane intetrahydrofuran (40 mL) maintaining a temperature of 0° C. After thecomplete addition the mixture was stirred at ambient temperature for 45min before a solution of tert-butyl piperidin-4-one-1-carboxylate (10 g,50 mmol) in tetrahydrofuran (40 mL) was slowly added at 0° C.Subsequently the reaction mixture was stirred for 18 h at ambienttemperature. Then saturated ammonium chloride solution was added and themixture was stirred vigorously until the dissolution of all solids. Thephases were separated and the aqueous was extracted with ethyl acetate.The combined organic phases were washed with brine, dried over magnesiumsulfate, filtered and concentrated under reduced pressure to give 16.42g of desired product (96%) as a yellow oil.

¹H NMR (360 MHz, CDCl₃): δ 4.16 (2H, s), 3.55 (2H, br m), 3.12 (211,ddd, J 3.8, 9.3, 12.8 Hz), 1.74-1.66 (2H, m), 1.53 (211, ddd, J 4, 9,12.8 Hz), 1.28 (9H, s).

(ii) tert-Butyl4-hydroxy-4-(3-hydroxyprop-1-yn-1-yl)piperidine-1-carboxylate

tert-Butyl4-hydroxy-4-{3-[(trimethylsilyl)oxy]prop-1-yn1-1-yl}piperidine-1-carboxylate(crude from step (i); 16.42 g, ca. 50 mmol) was stirred withtetrabutylammonium fluoride (90 mmol) in tetrahydrofuran (170 mL) atambient temperature for 18 h. Then the solvent was removed in vacuo andthe residue partitioned between water and ethyl acetate. The organicphase was separated and the aqueous was extracted with ethyl acetate.The combined organic phases were washed with brine, dried over magnesiumsulfate, filtered and concentrated under reduced pressure to give thecrude product as an amber oil, which was purified by flashchromatography on silica gel, eluting with 5% methanol indichloromethane to yield the desired diol (10.87 g, 85%).

¹H NMR (360 MHz, CDCl₃): δ 4.32 (2H, br s), 3.80-3.69 (2H, br m), 3.28(2H, ddd, J 3.5, 9.2, 13.2 Hz), 1.92-1.84 (2H, br m), 1.74 (2H, ddd, J3.8, 8.9, 12.7 Hz), 1.46 (9H, s).

(iii) tert-Butyl4-hydroxy-4-(3-hydroxyprop-1-ene-1-yl}piperidine-1-carboxylate

tert-Butyl 4-hydroxy-4-(3-hydroxyprop-1-yn-1-yl)piperidine-1-carboxylate(from step (ii); 10 g, 39.2 mmol) was stirred at ambient temperaturewith Lindlar's catalyst (5% Pd on CaCO₃ poisoned with Pb) (4.15 g, 2mmol of Pd) in ethanol under hydrogen (p≧1 atm) for 18 h. Then thecatalyst was filtered off and the filtrate concentrated under reducedpressure to give 10.2 g of the desired cis-olefin as a pale yellow oil.

¹H NMR (360 MHz, CDCl₃): δ 5.66-5.56 (2H, m), 4.33 (2H, d, J 5.2 Hz),3.77-3.67 (2H, m), 3.30-3.24 (2H, m), 1.73-1.63 (4H, m), 1.46 (9H, s).

(iv) tert-Butyl 1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate

To a solution of tert-butyl4-hydroxy-4-(3-hydroxyprop-1-ene-1-yl)piperidine-1-carboxylate (fromstep (iii); 8.79 g, 34.2 mmol) and triethylamine (7.6 g, 75.2 mmol) intetrahydrofuran (170 mL), methanesulfonyl chloride (4.31, 37.6 mmol) wasslowly added so that the internal temperature stayed between −10 and −5°C. After the complete addition the temperature was allowed to rise to12° C. and was kept at that temperature until all starting diol wasturned over (monitored by TLC (silica gel, 1:1 hexane/ethyl acetate)).Subsequently the reaction mixture was stirred for 2 days to complete thecyclisation before it was concentrated under reduced pressure. Theresidue was treated with water under ice-cooling, followed by extractionwith ethyl acetate. The combined organic layers were washed with brine,dried over magnesium sulfate, filtered and concentrated under reducedpressure to give 9 g of crude product as yellow oil. This was purifiedby flash chromatography on silica gel, eluting with a gradient solventsystem of 10-20% ethyl acetate in hexane to give 5.79 g of the desiredspirocyclic product (64%).

¹H NMR (360 MHz, CDCl₃): δ 5.88 (1H, ddd, J 1.7, 1.7, 6.1 Hz), 5.74 (1H,ddd, J 2.2, 2.2, 6.3 Hz), 4.64 (2H, dd, J 1.6, 2.2 Hz), 3.79-3.69 (2H,br m), 3.28 (2H, ddd, J 3.64, 10.5, 13.8 Hz), 1.68-1.54 (4H, m), 1.46(9H, s).

(v) tert-Butyl 1-oxa-8-aza[4.5]decan-3-ol-8-carboxylate

Borane-tetrahydrofuran-complex solution in tetrahydrofuran (16.7 mL, 1M.16.7 mmol) was added to a solution of tert-butyl1-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate (from step (iv) above; 2 g,8.37 mmol) in tetrahydrofuran (25 mT) at 0° C. After 1 h at roomtemperature, a mixture of 35% w/w hydrogen peroxide solution (6 mL, ca.67 mmol) and 4 M sodium hydroxide solution (17 mL) was slowly added at0° C. Then the reaction mixture was stirred at room temperature for 18 hbefore it was partitioned between water and ethyl acetate. The aqueousphase was extracted with ethyl acetate. The combined organic phases werewashed with saturated sodium sulfite solution, then brine and finallydried over magnesium sulfate, filtered and concentrated to give thecrude mixture of products as a colourless oil. The mixture was separatedby flash chromatography on silica gel, eluting with a gradient solventsystem of 50-100% ethyl acetate in hexane, then 1-2% methanol in ethylacetate to furnish 1.03 g of the title compound (48%).

¹H NMR (360 MB, CDCl₃): δ 4.51-4.49 (1H, m), 3.92 (1H, dd, J 4.4, 10.1Hz), 3.84-3.79 (1H, m), 3.59 (1H, br s), 3.38-3.30 (1H, m) 1.96 (1H, dd,J 6.3, 13.6 Hz), 1.85-1.79 (2H, m), 1.73-1.63 (2H, m), 1.58-1.50 (2H,m), 1.45 (9H, s).

(vi) 1-Oxa-8-aza[4.5]decan-3-ol trifluoroacetate

tert-Butyl 1-oxa-8-aza[4.5]decan-3-ol-8-carboxylate (from step (v)above; 1 g, 3.89 mmol) was stirred in a 1:1 v/v mixture oftrifluoroacetic acid and dichloromethane (8 mL) at ambient temperaturefor 0.5 h. The reaction mixture was concentrated in vacuo to give 1.55 gof a pale amber oil.

¹H NMR (360 MD, CDCl₃): δ 4.58-4.61 (1H, m), 3.87-4.02 (2H, m),3.37-3.47 (2H, m), 2.26-1.75 (6H, m); m/z (ES⁺) 158.

Description 23(2R,3R,4R,αRS)-α-(3-Buten-1-yl)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol

3-Butenylmagnesium bromide (0.5M in tetrahydrofuran, 75 mL, 37.5 mmol)was added slowly to a stirred, cooled −78° C. solution of(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxaldehyde(WO 00/56727A1; 11.1 g, 24.9 mmol) in tetrahydrofuran (125 mL). Themixture was stirred at −78° C. for 3 hours, then at room temperature for1.5 hour. Saturated aqueous ammonium chloride (20 mL) was added slowly,followed by ethyl acetate (300 mL). The layers were separated and theorganic layer was washed with brine (100 mL). The combined aqueouslayers were extracted with ethyl acetate (100 mL), the combined organiclayers were dried (Na₂SO₄), and the solvent was evaporated under reducedpressure. The residue was purified by column chromatography on silicagel, eluting with hexane/EtOAc (97:3 increasing to 80:20), to give thetitle compound (8:1 mixture of alcohol diastereoisomers) as a colorlessoil (10 g, 80%).

¹H NMR (500 MHz, CDCl₃) (major isomer described): δ 7.66 (1H, s),7.28-7.15 (5H, m), 7.04 (2H, m), 5.67 (1H, m), 4.94 (2H, m), 4.87 (1H,m), 4.25 (1H, d, J 8.6 Hz), 4.17 (1H, m), 3.53 (1H, m), 3.22 (1H, m),2.85 (1H, m), 2.01 (1H, m), 1.90 (1H, m), 1.78 (2H, m), 1.53 (2H, m),1.36 (3H, d, J 6.6 Hz), 1.31 (1H, m).

Description 24 (2R,3R,4R,αR orS)-α-(3-Buten-1-yl)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methylMethanesulfonate

Methanesulfonyl chloride (1.61 mL, 2.3 g, 21 mmol) was added dropwise toa stirred, cooled (−78° C.) solution of(2R,3R,4R,αRS)-α-(3-buten-1-yl)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol(Description 23, 8:1 mixture of diastereoisomers; 3.5 g, 6.97 mmol) andtriethylamine (5 mL, 3.5 g, 35 mmol) in dichloromethane (70 mL). Themixture was allowed to warm to room temperature over 1.5 hours, thenwater (20 mL) and ethyl acetate (100 mL) were added. The layers wereseparated and the organic layer was washed with brine (100 mL). Thecombined aqueous layers were extracted with ethyl acetate (100 mL), thecombined organic layers were dried (Na₂SO₄), and the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with hexane/EtOAc (95:5 increasingto 80:20), to give the title compound (single diastereoisomer) as acolorless oil (2.76 g, 68%).

¹H NMR (500 MHz, CDCl₃): δ 7.65 (1H, s), 7.25 (3H, m), 7.14 (2H, s),7.07 (2H, m), 5.62 (1H, m), 4.92 (3H, m), 4.39 (1H, t, J 6.6 Hz), 4.19(1H, m), 4.17 (1H, d, J 8.6 Hz), 3.54 (1H, dt, J 2.3, 11.0 Hz), 2.91(3H, s), 2.80 (1H, dd, J 8.3, 11.6 Hz), 2.15 (1H, m), 1.90 (3H, m), 1.80(1H, m), 1.68 (2H, m), 1.36 (3H, d, J 6.6 Hz).

Description 25 (2RS,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1,2,5-pentanetriol5-Methanesulfonate

2-Methyl-2-propanol (2 mL) was added to a solution of AD-mix-α (0.5 g)in water (2 mL) and the mixture was stirred vigorously at roomtemperature for 10 minutes. The yellow solution was then added to(2R,3R,4R,αR orS)-α-(3-buten-1-yl)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methylmethanesulfonate (Description 24; 0.24 g, 0.41 mmol) and the resultingmixture was stirred vigorously at room temperature overnight. Sodiumsulfite (2 g) was added and the mixture was stirred for 30 minutes.Water (10 mL) and ethyl acetate (10 mL) were added, the layers wereseparated and the organic layer was washed with brine (100 mL). Thecombined aqueous layers were extracted with ethyl acetate (100 mL), thecombined organic layers were dried (Na₂SO₄), and the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with hexane/EtOAc (50:50increasing to 10:90), to give the title compound (3:1 mixture of alcoholdiastereoisomers) as a colorless oil (0.20 g, 79%). ¹H NMR (500 MHz,CD₃OD): δ 7.70 (1H, s), 7.30 (2H, s), 7.21 (3H, m), 7.17 (2H, m), 5.00(1H, q, J 6.5 Hz), 4.33 (2H, m), 4.10 (1H, m), 3.65 (1H, m), 3.35 (3H,m), 3.03, 3.02 (3H, each s), 2.78 (1H, dd, J 8.3, 11.6 Hz), 2.27 (1H,m), 1.90-1.40 (6H, m), 1.33 (3H, d, J 6.6 Hz).

Description 26 (2RS,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1,2,5-pentanetriol5-Methanesulfonate

The title compound (1:3 mixture of alcohol diastereoisomers) wasprepared from (2R,3R,4R,αR orS)-α-(3-buten-1-yl)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methylmethanesulfonate (Description 24) according to the method of Description25, using AD-mix-O instead of AD-mix-α. ¹H NMR (500 MHz, CD₃OD): δ 7.70(1H, s), 7.30 (2H, s), 7.21 (3H, m), 7.17 (2H, m), 5.00 (1H, q, J 6.5Hz), 4.33 (2H, m), 4.10 (1H, m), 3.65 (1H, m), 3.35 (3H, m), 3.03, 3.02(3H, each s), 2.78 (1H, dd, J 8.3, 11.6 Hz), 2.27 (1H, m), 1.90-1.40(6H, m), 1.33 (3H, d, J 6.6 Hz).

Description 27 (2RS,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1,2,5-pentanetriol1-(4-Methylbenzenesulfonate) 5-Methanesulfonate

4-Methylbenzenesulfonyl chloride (53 mg, 0.28 mmol) was added to amixture of (2RS,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-1,2,5-pentanetriol5-methanesulfonate (3:1 mixture of alcohol diastereoisomers; Description25; 0.17 g, 0.28 mmol), dibutyltin oxide (1.4 mg, 5.6 μmol) andtriethylamine (39 μL, 0.28 mmol) in dichloromethane (1.4 mL) and themixture was stirred vigorously at room temperature for 3 hours. Thesolvent was evaporated under reduced pressure and the residue waspurified by column chromatography on silica gel, eluting withhexane/EtOAc (80:20 increasing to 50:50), to give the title compound(3:1 mixture of alcohol diastereoisomers) as a colorless oil (0.142 g,67%).

¹H NMR (500 MHz, CD₃OD): δ 7.75 (2H, d, J 8.2 Hz), 7.71 (1H, s), 7.40(2H, d, J 8.2 Hz), 7.30 (2H, s), 7.20 (3H, m), 7.13 (2H, m), 5.00 (1H,q, J 6.5 Hz), 4.32 (1H, d, J 8.5 Hz), 4.26 (1H, t, J 6.4 Hz), 4.11 (1H,m), 3.85-3.75 (2H, m), 3.62 (2H, m), 3.47 (1H, m), 3.01, 3.00 (3H, eachs), 2.74 (1H, dd, J 8.3, 11.6 Hz), 2.43 (3H, s), 2.20 (1H, m), 1.90-1.40(6H, m), 1.33 (3H, d, J 6.6 Hz).

Description 28 (2RS,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1,2,5-pentanetriol1-(4-Methylbenzenesulfonate) 5-Methanesulfonate

The title compound (1:3 mixture of alcohol diastereoisomers) wasprepared from (2RS,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-1,2,5-pentanetriol5-methanesulfonate (1:3 mixture of alcohol diastereoisomers; Description26) according to the method of Description 27.

¹H NMR (500 MHz, CD₃OD): δ 7.75 (2H, d, J 8.2 Hz), 7.71 (1H, s), 7.40(2H, d, J 8.2 Hz), 7.30 (2H, s), 7.20 (3H, m), 7.13 (2H, m), 5.00 (1H,q, J 6.5 Hz), 4.32 (1H, d, J 8.5 Hz), 4.26 (1H, t, J 6.4 Hz), 4.11 (1H,m), 3.85-3.75 (2H, m), 3.62 (2H, m), 3.47 (1H, m), 3.01, 3.00 (3H, eachs), 2.74 (1H, dd, J 8.3, 11.6 Hz), 2.43 (3H, s), 2.20 (1H, m), 1.90-1.40(6H, m), 1.33 (3H, d, J 6.6 Hz).

Description 29(2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2Ror S)-oxiranyl]-3-phenyl-2H-pyran; and(2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2Sor R)-oxiranyl]-3-phenyl-2H-pyran (Isomers A and E)

Dimethylsulfoxide (10 mL) was added to sodium hydride (60% dispersion inmineral oil, 385 mg, 9.6 mmol) and the mixture was stirred at roomtemperature for 30 minutes. Tetrahydrofuran (20 mL) was added and themixture was cooled to −10° C. Trimethylsulfonium iodide (2.13 g, 10.4mmol) in dimethylsulfoxide (10 mL) was added and the mixture was stirredat 0° C. for 10 minutes.(2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxaldehyde(WO 00/56727A1; 3.58 g, 8.0 mmol) in tetrahydrofuran (10 mL) was addedand the mixture was stirred at 0° C. for 30 minutes, then at roomtemperature for 30 minutes. Water (100 mL) was added and the mixture wasextracted with ethyl acetate (3×100 mL). The combined organic fractionswere washed with water (4×100 mL) and brine (100 mL), dried (MgSO₄) andthe solvent was evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel, eluting withhexane/EtOAc (85:15 increasing to 80:20), to give(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2Ror S)-oxiranyl]-3-phenyl-2H-pyran (Isomer A; single diastereoisomer;epoxide stereochemistry unassigned) as a colorless oil (1.37 g, 37%); ¹HNMR (500 MHz, CDCl₃): δ 7.67 (1H, s), 7.23 (5H, m), 7.01 (2H, m), 4.97(1H, q, J 6.6 Hz), 4.28 (1H, d, J 8.4 Hz), 4.16 (1H, br d, J 11 Hz),3.53 (1H, br t, J 11 Hz), 2.65 (1H, dd, J 8.4 Hz), 2.60 (1H, m), 2.34(1H, t, J 4.5 Hz), 1.95 (1H, dd, J 4.5, 2.7 Hz), 1.84 (1H, br d, J 11Hz), 1.68 (1H, m), 1.57 (1H, m), 1.37 (3H, d, J 6.6 Hz); and(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2Sor R)-oxiranyl]-3-phenyl-2H-pyran (Isomer B; single diastereoisomer;epoxide stereochemistry unassigned) as a colorless oil (0.51 g, 14%); ¹HNMR (500 Mb, CDCl₃): δ 7.67 (1H, s), 7.27-7.20 (5H, m), 7.08 (2H, m),4.96 (1H, q, J 6.6 Hz), 4.25 (1H, d, J 8.3 Hz), 4.13 (1H, br d, J 12Hz), 3.54 (1H, br t, J 12 Hz), 2.68 (1H, m), 2.61 (1H, dd, J 11.5, 8.3Hz), 2.50 (1H, t, J 4.6 Hz), 2.46 (1H, dd, J 4.6, 2.8 Hz), 2.03 (1H, m),1.60 (1H, br d, J 12 Hz), 1.49 (1H, m), 1.37 (3H, d, J 6.6 Hz); and a1:1 mixture of Isomer A and Isomer B (1.16 g, 31%).

Description 30 (2R,3R,4R,αR orS)-α-{[(2-Hydroxyethyl)thio]methyl}-2-{(1R)-1-[3,5-bio(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol;and (2R,3R,4R,αS orR)-α-{[(2-hydroxyethyl)thio]methyl}-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol

2-Mercaptoethanol (0.70 mL, 0.78 g, 10 mmol) was added to a degassedmixture of(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2Ror S)-oxiranyl]-3-phenyl-2H-pyran and(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)-phenyl]ethoxy}tetrahydro-4[(2Sor R)-oxiranyl]-3-phenyl-2H-pyran (Description 29, 1:1 mixture ofdiastereoisomers; 0.46 g, 1 mmol) and potassium hydroxide (0.56 g, 10mmol) in propan-2-ol (10 mL) and the mixture was heated under reflux for4 hours. The mixture was cooled and the solvent was evaporated underreduced pressure. Aqueous sodium hydroxide (1M, 20 mL) was added and themixture was extracted with diethyl ether (3×20 mL). The combined organicfractions were washed with aqueous sodium hydroxide (1M, 2×20 mL) andbrine (20 mL), dried (MgSO₄) and the solvent was evaporated underreduced pressure to give the title compound (1:1 mixture of alcoholepimers) as a yellow oil (0.54 g, 100%).

¹H NMR (500 MHz, CDCl₃): δ 7.66 (1H, s), 7.26-7.23 (3H, m), 7.18 and7.15 (2H, each s), 7.05 (2H, m), 4.95 (1H, m), 4.25, 4.23 (1H, each d, J8.3 Hz), 4.18 (1H, m), 3.62-3.53 (3H, m), 3.30 (1H, m), 2.90-1.51 (10H,m), 1.36 (3H, d, J 6.6 Hz).

Description 31(2R,3R,4R,αR)-α-2-Propenyl-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol

Allylmagnesium bromide (15.4 mL, 15.4 mmol) was slowly added to astirred, cooled −40° C. solution ofchlorobis[(1S,2R,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]borane(5.91 g, 18 mmol) in diethyl ether (20 mL). The mixture was warmed toroom temperature and stirred for 1 hour before cooling to −78° C.(2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxaldehyde(WO 00/56727A1; 5.5 g, 12.3 mmol) in diethyl ether (10 mL) was slowlyadded and the mixture was stirred at −78° C. for 1.5 hours. The mixturewas warmed to room temperature and stirred for a further 1.5 hours. Themixture was cooled to −78° C. and aqueous sodium acetate (3M, 20 mL)then aqueous hydrogen peroxide (31% wt, 10 mL) were added. The mixturewas allowed to warm to room temperature and stirred overnight. Thelayers were separated and the aqueous layer was extracted with ethylacetate (2×150 mL). The combined organic fractions were dried (MgSO₄)and the solvent was evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel, eluting withEtOAc/hexane (90:10), to give the title compound as a yellow oil (4.7 g,78%).

¹H NMR (360 MHz, CDCl₃): δ 1.25 (3H, d, J 7 Hz), 1.34 (1H, d, J 6.6 Hz),1.54 (1H, d, J 9 Hz), 1.80 (1H, m), 2.05 (1H, m), 2.14 (1H, m), 2.88(1H, m), 3.27 (1H, m), 3.53 (1H, m), 4.17 (1H, m), 4.25 (1H, d, J 8.6Hz), 4.94-4.98 (2H, m), 5.03 (1H, m), 5.60 (1H, m), 7.03-7.05 (2H, m),7.18-7.24 (5H, m), 7.65 (1H, s).

Description 32(2R,3R,4R,αS)-α-2-Propenyl-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol

Prepared from(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-carboxaldehyde(WO 00/56727A1), allylmagnesium bromide andchlorobis[(1R,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]boraneaccording to the method of Description 31.

¹H NMR (360 MHz, CDCl₃): δ 1.36 (3H, d, J 6.6 Hz), 1.58 (1H, m), 1.80(1H, m), 1.95 (1H, m), 2.17 (1H, m), 2.23 (1H, m), 2.55 (1H, m), 3.30(1H, m), 3.55 (1H, m), 4.17 (1H, m), 4.23 (1H, d, J 8.2 Hz), 4.94 (1H,m), 5.03-5.06 (2H, m), 5.59 (1H, m), 7.03-7.04 (2H, m), 7.05 (2H, m),7.16-7.24 (3H, m), 7.69 (1H, s), 7.85 (1H, s).

Description 33(1R)-1-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-1,3-propanediol

(2R,3R,4R,αR)-α-2-Propenyl-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-methanol(Description 31; 1.0 g, 2 mmol) was dissolved indichloromethane/methanol (1:1, 30 mL), cooled to −78° C. and purged withnitrogen and then oxygen. Ozone was bubbled through the mixture for15-20 minutes, until a blue coloration persisted. The mixture was purgedwith oxygen, then nitrogen, warmed to 0° C. and sodium borohydride (0.3g, 8 mmol) was added in portions. The mixture was stirred at 0° C. for30 minutes, aqueous ammonium chloride (10%, 40 mL) was added and themixture was extracted with dichloromethane (2×75 mL). The combinedorganic fractions were dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with EtOAc/hexane (50:50) to givethe title compound as a colorless oil (0.5 g, 50%).

¹H NMR (500 MHz, CD₃OD): δ 1.32 (3H, d, J 6.6 Hz), 1.41 (1H, m), 1.55(1H, m), 1.62 (1H, m), 1.75 (1H, m), 1.86 (1H, m), 2.81 (1H, dd, J 8.6,11.5 Hz), 3.45-3.51 (2H, m), 3.62 (1H, dt, J_(d) 2.3, J_(t) 12.0 Hz),4.1 (1H, m), 4.36 (1H, d, J 8.7 Hz), 4.99 (1H, q, J 6.5 Hz), 7.09-7.11(2H, m), 7.16-7.21 (3H, m), 7.31 (2H, s), 7.70 (1H, s).

Description 34(1S)-1-((2R,3R,4R)-(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-1,3-propanediol

Prepared from(2R,3R,4R,αS)-α-2-propenyl-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol(description 32) according to the method of Description 33.

¹H NMR (360 MHz, CDCl₃): δ 1.35 (3H, d, J 6.6 Hz), 1.57-1.60 (3H, m),1.80 (1H, m), 1.95 (1H, m), 2.06 (1H, m), 2.43 (1H, m), 2.50 (1H, m),3.54-3.57 (3H, m), 3.80 (1H, m), 4.23 (1H, m), 4.24 (1H, d, J 8.1 Hz),4.93 (1H, m), 7.02-7.04 (2H, m), 7.16-7.23 (5H, m), 7.65 (1H, s).

Description 35(1R)-1-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-1,3-propanediolDimethylsulfonate

(1R)-1-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-yl)-1,3-propanediol(Description 33; 0.5 g, 1 mmol) was dissolved in dichloromethane (5 mL)and cooled to −10° C. Triethylamine (0.56 mL, 4 mmol) was added followedby methanesulfonyl chloride (0.23 mL, 3 mmol) dropwise. The mixture wasstirred at −20° C. for 30 minutes, then at room temperature for 15minutes. Water (75 mL) was added and the mixture was extracted withdichloromethane (3×75 mL). The combined organic fractions were dried(MgSO₄) and the solvent was evaporated under reduced pressure to givethe title compound as a colorless foam (0.65 g, 100%).

¹H NMR (500 MHz, CDCl₃): δ 1.35 (3H, d, J 6.7 Hz), 1.65 (1H, m), 1.77(1H, m), 2.05 (1H, m), 2.15-2.20 (2H, m), 2.75 (1H, m), 2.84 (3H, s),2.92 (3H, s), 3.55 (1H, t, J 12 Hz), 4.15-4.22 (4H, m), 4.55 (1H, m),4.92 (1H, q, J 6.5 Hz), 7.09-7.13 (4H, m), 7.24-7.26 (3H, m), 7.65 (1H,s).

Description 36(1S)-1-((2R,3R,4R)-1-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-1,3-propanediolDimethylsulfonate

Prepared from(1S)-1-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1,3-propanediol(Description 34) according to the method of Description 35.

¹H NMR (400 MHz, CDCl₃): δ 1.35 (3H, d, J 6.6 Hz), 1.60 (1H, m),1.80-1.90 (2H, m), 1.99 (1H, m), 2.48 (1H, m), 2.55 (1H, m), 2.72 (3H,s), 2.92 (3H, s), 3.60 (1H, m), 4.1 (1H, m), 4.20-4.22 (3H, m), 4.45(1H, m), 4.48 (1H, m), 7.08-7.14 (4H, m), 7.26-7.29 (3H, m), 7.66 (1H,s).

Description 37Methyl(2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-carboxylate

Trimethylsilyldiazomethane (2.0M in hexanes, 3.5 mL, 7 mmol) was addedin portions over 1 hour to a solution of(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxylicacid (WO 00/56727A1; 3.2 g, 6.9 mmol) in a mixture of methanol (10 mL)and toluene (7 mL). The solvent was evaporated under reduced pressureand the residue was purified by column chromatography on silica gel,eluting with EtOAc/hexane (80:20), to give the title compound as acolorless solid (2.4 g, 73%).

¹H NMR (500 MHz, CDCl₃): δ 7.67 (1H, s), 7.22 (5H, m), 7.07 (2H, m),4.96 (1H, q, J 6.6 Hz), 4.28 (1H, d, J 8.2 Hz), 4.17 (1H, br d, J 11Hz), 3.58 (1H, br t, J 11 Hz), 3.45 (3H, s), 3.04 (1H, dd, J 8.2, 11.4Hz), 2.81 (1H, br t, J 11 Hz), 1.94 (1H, br q, J 11 Hz), 1.86 (1H, br d,J 11 Hz), 1.38 (3H, d, J 6.6 Hz).

Description 38(2R,3R,4R)-α,α-Di-(2-propenyl)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol

Allylmagnesium bromide (1.0M in hexanes, 8.8 mL, 8.8 mmol) was addedslowly to a stirred, cooled (0° C.) solution ofmethyl(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxylate(Description 37; 1.4 g, 2.9 mmol) in tetrahydrofuran (10 mL). Themixture was warmed to room temperature and stirred for 30 minutes.Saturated aqueous ammonium chloride (50 mL) was added and the mixturewas extracted with ethyl acetate (3×30 mL). The combined organicfractions were dried (MgSO₄) and the solvent was evaporated underreduced-pressure. The residue was purified by column chromatography onsilica gel, eluting with EtOAc/hexane (80:20), to give the titlecompound as a colorless oil (1.48 g, 95%).

¹H NMR (400 MHz, CDCl₃): δ 7.66 (1H, s), 7.22 (3H, m), 7.16 (2H, s),7.11 (2H, m), 5.88-5.70 (2H, m), 5.08-4.97 (4H, m), 4.89 (1H, q, J 6.6Hz), 4.22 (1H, d, J 7.7 Hz), 4.15-4.09 (1H, m), 3.50 (1H, br t, J 12Hz), 2.84 (1H, dd, J 10.9, 7.7 Hz), 2.21-2.11 (5H, m), 1.78 (1H, br d, J12 Hz), 1.64 (1H, br q, J 12 Hz), and 1.35 (3H, d, J 6.6 Hz).

Description 393-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1,3,5-propanetriol

(2R,3R,4R)-α,α-Di-(2-propenyl)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-methanol(Description 39; 1.48 g, 2.8 mmol) was dissolved indichloromethane/methanol (1:1, 30 mL), cooled to −78° C. and purged withnitrogen and then oxygen. Ozone was bubbled through the mixture for15-20 minutes, until a blue coloration persisted. The mixture was purgedwith oxygen, then nitrogen, warmed to 0° C. and sodium borohydride (0.21g, 5.6 mmol) was added in portions. The mixture was stirred at 0° C. for30 minutes, aqueous ammonium chloride (10%, 50 mL) was added and themixture was extracted with dichloromethane (2×50 mL). The combinedorganic fractions were dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with EtOAc/hexane (50:50), to givethe title compound as a colorless oil (0.80 g, 55%).

¹H NMR (400 MHz, CDCl₃): δ 7.66 (1H, s), 7.19 (3H, m), 7.14 (2H, s),7.04 (2H, m), 4.89 (1H, q, J 6.6 Hz), 4.25 (1H, d, J 8.0 Hz), 4.17 (1H,br d, J 11 Hz), 3.80 (2H, br s), 3.70(1H, br m), 3.56 (2H, m), 3.40 (1H,s), 3.24 (1H, br s), 2.84 (1H, br s), 2.72 (1H, dd, J 11.3, 8.0 Hz),2.37 (1H, br t, J 11 Hz), 1.89-1.80 (2H, m), 1.70-1.56 (3H, m), 1.34(3H, d, J 6.6 Hz), 1.19-1.13 (1H, m).

Description 403-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1,3,5-propanetriol1,5-Dimethylsulfonate

Methanesulfonyl chloride (0.24 mL, 0.36 g, 3.2 mmol) was added slowly toa stirred, cooled (−10° C.) solution of3-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1,3,5-propanetriol(Description 39; 0.80 g, 1.5 mmol) and triethylamine (0.48 mL, 0.35 g,3.5 mmol) in dichloromethane (8 mL). The mixture was stirred at −10° C.for 20 minutes, then water (25 mL) was added and the mixture wasextracted with dichloromethane (3×30 mL). The combined organic fractionswere washed with aqueous citric acid (10%, 30 mL) and saturated aqueoussodium carbonate (30 mL), dried (MgSO₄) and the solvent was evaporatedunder reduced pressure to give the title compound as a colorless foam(1.0 g, 100%).

¹H NMR (500 MHz, CDCl₃): δ 7.67 (1H, s), 7.28 (3H, m), 7.13 (4H, m),4.90 (1H, q, J 6.6 Hz), 4.34-4.15 (6H, m), 3.68 (1H, s), 3.58 (1H, br t,J 11 Hz), 2.97 (3H, s), 2.95 (3H, s), 2.78 (1H, m), 2.22 (1H, br t, J 11Hz), 1.97-1.94 (3H, m), 1.83-1.76 (2H, m), 1.61 (1H, m), 1.35 (3H, d, J6.6 Hz).

Description 41(2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2Ror S)-oxiranyl]-3-phenyl-2H-pyran; and(2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2Sor R)-oxiranyl]-3-phenyl-2H-pyran (Isomers A and B)

Dimethylsulfoxide (10 mL) was added to sodium hydride (60% dispersion inmineral oil, 385 mg, 9.6 mmol) and the mixture was stirred at roomtemperature for 30 minutes. Tetrahydrofuran (20 mL) was added and themixture was cooled to −10° C. Trimethylsulfonium iodide (2.13 g, 10.4mmol) in dimethylsulfoxide (10 mL) was added and the mixture was stirredat 0° C. for 10 minutes.(2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxaldehyde(WO 00/56727A1; 3.58 g, 8.0 mmol) in tetrahydrofuran (10 mL) was addedand the mixture was stirred at 0° C. for 30 minutes, then at roomtemperature for 30 minutes. Water (100 mL) was added and the mixture wasextracted with ethyl acetate (3×100 mL). The combined organic fractionswere washed with water (4×100 mL) and brine (100 mL), dried (MgSO₄) andthe solvent was evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel, eluting withhexane/EtOAc (85:15 increasing to 80:20), to give:(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2Ror S)-oxiranyl]-3-phenyl-2H-pyran (Isomer A; single diastereoisomer;epoxide stereochemistry unassigned) as a colorless oil (1.37 g, 37%); ¹HNMR (500 MHz, CDCl₃): δ 7.67 (1H, s), 7.23 (5H, m), 7.01 (2H, m), 4.97(1H, q, J 6.6 Hz), 4.28 (1H, d, J 8.4 Hz), 4.16 (1H, br d, J 11 Hz),3.53 (1H, br t, J 11 Hz), 2.65 (1H, dd, J 8.4 Hz), 2.60 (1H, m), 2.34(1H, t, J 4.5 Hz), 1.95 (1H, dd, J 4.5, 2.7 Hz), 1.84 (1H, br d, J 11Hz), 1.68 (1H, m), 1.57 (1H, m), 1.37 (311, d, J 6.6 Hz); and(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-4-[(2Sor R)-oxiranyl]-3-phenyl-2H-pyran (Isomer B; single diastereoisomer;epoxide stereochemistry unassigned) as a colorless oil (0.51 g, 14%); ¹HNMR (500 MHz, CDCl₃): δ 7.67 (1H, s), 7.27-7.20 (5H, m), 7.08 (2H, m),4.96 (1H, q, J 6.6 Hz), 4.25 (1H, d, J 8.3 Hz), 4.13 (1H, br d, J 12Hz), 3.54 (1H, br t, J 12 Hz), 2.68 (1H, m), 2.61 (1H, dd, J 11.5, 8.3Hz), 2.50 (1H, t, J 4.6 Hz), 2.46 (1H, dd, J 4.6, 2.8 Hz), 2.03 (1H, m),1.60 (1H, br d, J 12 Hz), 1.49 (1H, m), 1.37 (3H, d, J 6.6 Hz); and a1:1 mixture of Isomer A and Isomer B (1.16 g, 31%).

EXAMPLE 1(4R)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-3-aza-spiro[4.5]decan-4-ol

(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylicacid(4R)-8-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]dec-4-ylester (Description 14; 130 mg, 0.15 mmol) was dissolved indichloromethane (3 ml) and the solution was cooled to −78° C. undernitrogen. A solution of diisobutylaluminium hydride (0.9 ml, 1M intoluene) was added dropwise and the solution was stirred for 30 min.Methanol (0.1 ml) was added dropwise and the resulting quenched solutionwas poured carefully onto sodium hydroxide (10 ml, 4M. This was stirredfor 30 min. The organic extracts were pooled, washed with brine, dried(MgSO₄) and concentrated in vacuo. The residue was purified bychromatography on silica gel using 1-5% methanol in dichloromethane aseluant. This afforded the product as a white foam (96 mg, 93%).

This was further purified by recrystallisation of the HCl salt fromether-dichloromethane to give the product as white crystals (86 mg).

¹H NMR (500 MHz, CDCl₃): δ 7.69 (1H, s), 7.23 (1H, dd, J 2.1, 6.5 Hz),7.21 (2H, s), 6.98 (1H, t, J 8.3 Hz), 6.89-6.92 (1H, m), 4.95(1H, q, J6.5 Hz), 4.10-4.14 (2H, m), 4.03 (1H, dd, J 4.6, 10.0 Hz), 3.90 (1H, dd,J 1.7, 4.4 Hz), 3.65 (1H, dd, J 2.2, 10.0 Hz), 3.59 (1H, d, J 8.5 Hz),3.54 (1H, d, J 8.5 Hz), 3.51 (1H, dd, J 12.1, 2.0 Hz), 2.39-2.37 (1H,m), 2.37 (1H, dd, J 8.3, 11.0 Hz), 2.28-2.20 (1H, m), 2.12-1.84 (6H, m),1.73-1.68 (1H, m), 1.49-1.43 (2H, m), 1.39 (3H, d, J 6.6 Hz); m/z (ES⁺)684 (M⁺+1, 95%), 686 (M⁺+1, 100%).

EXAMPLE 2(4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol

Triethylamine (140 μL, 1.0 mmol) was added to a suspension of2-oxa-8-aza-spiro[4.5]decan-4-ol hydrochloride (Description 8; 0.1 g,0.54 mmol) in 1,2-dichloroethane (2 ml). After 10 minutes,(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-carbaldehyde(see Example 43 in WO 00/56727; 0.24 g, 0.54 mmol) was added as asolution in 1,2-dichloroethane (3 ml). The mixture was stirred at roomtemperature for 30 minutes then sodium triacetoxyborohydride (0.2 g,0.94 mmol) was added. The reaction was stirred at room temperatureovernight. The mixture was partitioned between dichloromethane andbrine. The organic layer was dried (MgSO₄) and concentrated in vacuo.The residue was purified by preparative thin layer chromatography,eluting with 5% methanol/dichloromethane, to give the title compound (72mg, 23%).

¹H NMR (400 MB, CDCl₃): δ 7.58 (1H, s), 7.16-7.15 (3H, m), 7.09 (2H, s),6.95-6.92 (2H, m), 4.87 (1H, q, J 6.6 Hz), 4.12 (1H, d, J 8.3 Hz), 4.07(1H, dd, J 3.5, 11.7 Hz), 3.96-3.93 (1H, m), 3.83-3.81 (1H, m),3.59-3.43 (4H, m), 2.41-2.38 (1H, m), 2.34-2.29 (1H, m), 2.21-2.15 (1H,m), 2.05-1.85 (5H, m), 1.74-1.66 (2H, m), 1.45-1.34 (4H, m), 1.29 (3H,d, J 6.6 Hz).

EXAMPLE 3(4S)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol

A solution of(1S,4R)-4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylicacid(4RS)-8-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]decylester (Description 12; 138 mg, 0.175 mmol) in dichloromethane (5 ml) wascooled to −78° C. and diisobutylaluminium hydride (1.5M in toluene, 0.5ml, 0.75 mmol) added. The reaction was stirred for 30 minutes thenquenched by the addition of 2M aqueous sodium hydroxide solution. Themixture was allowed to warm to room temperature then dried over Na₂SO₄and filtered through Celite™. The filtrate was concentrated in vacuo andthe residue purified by preparative thin layer chromatography, elutingwith 7% methanol/dichloromethane to give the title compound (27 mg,26%).

¹H NMR (360 MHz, CDCl₃): δ 7.67 (1H, s), 7.17 (2H, s), 7.00-6.92 (4H,m), 4.95 (1H, q, J 6.5 Hz), 4.15-4.11 (2H, m), 4.04-4.00 (1H, m),3.90-3.89 (1H, m), 3.67-3.60 (2H, m), 3.54-3.48 (2H, m), 2.52-2.42 (1H,m), 2.41-2.36 (1H, m), 2.34-2.14 (2H, m), 2.10-1.87 (4H, m), 1.86-1.76(1H, m), 1.75-1.67 (1H, m), 1.55-1.40 (4H, m), 1.36 (3H, d, J 6.5 Hz);m/z (ES+) 606 (M+H)⁺.

EXAMPLE 4(4R)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol

The title compound was prepared from(1S,4R)-4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylicacid(4R)-8-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]decylester (Description 13) according to the method of Example 3.

¹H NMR (360 MHz, CDCl₃): δ 7.67 (1H, s), 7.17 (2H, s), 7.03-6.89 (4H,m), 4.95 (1H, q, J 6.6 Hz), 4.13 (2H, m), 4.02 (1H, dd, J 4.7, 9.8 Hz),3.90 (1H, m), 3.65 (1H, dd, J 2.0, 10.2 Hz), 3.59 (1H, d, J 8.2 Hz),3.53 (1H, dd, J 8.6 Hz), 3.50 (1H, dd, J 1.6, 12.1 Hz), 2.57-1.52 (11H,m), 1.60-1.40 (4H, m), 1.36 (3H, d, J 6.5 Hz); m/z (ES+) 606 (M+H)⁺.

EXAMPLE 5(4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol

A mixture of methanesulfonic acid[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methylester (Description 16; 0.275 g, 0.49 mmol),2-oxa-8-aza-spiro[4.5]decan-4-ol hydrochloride (Description 8; 0.1 g,0.37 mmol), potassium carbonate (237 g, 1.7 mmol) and acetonitrile (3ml) was stirred at 55° C. overnight and then at 65° C. for 18 hours. Themixture was treated with water and extracted into dichloromethane. Thecombined organic extracts were dried (Na₂SO₄) and concentrated. Theresidue was purified by preparative TLC (dichloromethane:methanol) togive the title compound.

m/z (ES+) 624 (M+H)⁺.

EXAMPLE 68-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-3-aza-spiro[4.5]decane

A mixture of2-[1-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde(Description 11; 0.15 g, 0.32 mmol), 2-oxa-8-azaspiro[4.5]decanehydrochloride (0.85 g, 0.48 mmol), triethylamine (50 μL, 0.49 mmol),sodium triacetoxyborohydride (0.136 g, 0.64 mmol) and dichloroethane (3ml) was stirred at room temperature for 2 hours. The mixture was treatedwith sodium bicarbonate and extracted into dichloromethane. The combinedorganic extracts were dried (Na₂SO₄) and concentrated. The residue waspurified by chromatography on alumina (grade E) using ethyl acetate inhexane (10-50%) to give the title compound.

¹H NMR (360 MHz, CDCl₃): δ 1.36 (3H, d, J 6.6 Hz), 1.38-1.55 (5H, m),1.61 (2H, t, J 7.1 Hz), 1.82-2.05 (6H, m), 2.18-2.31 (2H, m), 2.37 (1H,dd, J 10.5, 8.4 Hz), 3.43 (2H, s), 3.51 (1H, br t), 3.77 (2H, t, J 7.1Hz), 4.10-4.14 (2H, m), 4.95 (1H, q, J 6.6 Hz), 6.91-7.01 (4H, m), 7.17(2H, s), 7.67 (1H, s); m/z (ES+) 591 (M⁺+H, 100%).

EXAMPLE 78-[(2R,3S,4S)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran-4-yl)]methyl-1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane

A mixture of(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde(see Example 43 in WO 00/56727) and1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane (Bioorg. and Med. Chem. Lett.2002, 12, 1759) was reacted and purified according to the proceduredescribed in Example 6 to give the title compound.

¹H NMR (360 MHz, CDCl₃): δ 1.07 (3H, s), 1.08 (3H, s), 1.20-1.37 (3H,m), 1.46 (3H, d, J 6.6 Hz), 1.50-1.64 (3H, m), 1.78-1.91 (3H, m),2.0-2.15 (3H, m), 2.57-2.71 (3H, m), 2.97-3.02 (1H, m), 3.72-3.79 (3H,m), 4.04-4.10 (1H, m), 4.41 (1H, d, 3.2 Hz), 4.95 (1H, q, J 6.6 Hz),7.24-7.26 (5H, m), 7.36 (2H, s), 7.67 (1H, s); m/z (ES+) 600 (M⁺+H,100%)

EXAMPLE 88-[(2R,3S,4S)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran-4-yl)]methyl-2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane

A mixture of(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde(see Example 43 in WO 00/56727) and2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane (Description 18) was reactedand purified according to the procedure described in Example 6 to givethe title compound.

¹H NMR (360 MHz, CDCl₃): δ 1.20 (6H, s), 1.44 (3H, d, J 6.6 Hz),1.46-1.55 (4H, m), 1.60-1.71 (1H, m), 1.72-1.82 (4H, m), 1.82-1.95 (1H,m), 1.95-2.18 (3H, m), 2.25-2.38 (2H, m), 2.50-2.65 (3H, m), 3.73-3.75(1H, m), 3.97-4.04 (1H, m), 4.41 (1H, d, 2.3 Hz), 4.87 (1H, q, J 6.6Hz), 7.18 (2H, s) 7.18-7.32 (5H, m), 7.58 (1H, s); m/z (ES+) 600 (M⁺+H,100%)

EXAMPLE 98-[(2R,3S,4S)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1-oxa-8-aza-spiro[4.5]decane

A mixture of(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde(see Example 43 in WO 00/56727) and 1-oxa-8-aza-spiro[4.5]decane(Description 17) was reacted and purified according to the proceduredescribed in Example 6 to give the title compound.

¹H NMR (360 MHz, CDCl₃): δ 1.45 (3H, d, J 6.6 Hz), 1.46-1.70 (7H, m),1.86-2.32 (7H, m), 2.40-2.75 (4H, m), 3.73-3.78 (3H, m), 4.04-4.10 (1H,m), 4.41 (1H, d, 3.0 Hz), 4.95 (1H, q, J 6.6 Hz), 7.18-7.29 (5H, m) 7.35(2H, s), 7.67 (1H, s); m/z (ES+) 572 (M⁺+H, 100%).

EXAMPLE 108-[(2R,3S,4S)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane

A mixture of(2R,3S,4S)-2-[(1R)-3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde(see Example 43 in WO 00/56727) and 2-oxa-8-aza-spiro[4.5]decane(Bioorg. and Med. Chem. Lett. 2002, 12, 1759) was reacted and purifiedaccording to the procedure described in Example 6 to give the titlecompound.

¹H NMR (360 MHz, CDCl₃): δ 1.45 (3H, d, J 6.6 Hz), 1.48-1.70 (5H, m),1.66 (2H, t, J 7.1 Hz), 1.86-1.98 (1H, m), 2.01-2.20 (4H, m), 2.36-2.48(2H, m), 2.56 (1H, dd, J 11.9, 3.0 Hz), 2.58-2.70 (1H, m), 3.48 (2H, s),3.75 (1H, dd, J 11.1, 3.7 Hz), 3.81 (2H, t, J 7.1 Hz), 3.97-4.04 (1H,m), 4.42 (1H, d, J 3.0 Hz), 4.87 (1H, q, J 6.6 Hz), 7.18 (2H, s),7.19-7.29 (5H, m), 7.59 (1H, s); m/z (ES+) 572 (M⁺+H, 100%).

EXAMPLE 118-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane

A mixture of(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde(see Example 45 in WO 00/56727) and 2-oxa-8-aza-spiro[4.5]decane(Bioorg. and Med. Chem. Lett. 2002, 12, 1759) was reacted and purifiedaccording to the procedure described in Example 6 to give the titlecompound.

¹H NMR (360 MHz, CDCl₃): δ 1.35 (3H, d, J 6.6 Hz), 1.40-1.50 (3H, m),1.60 (2H, t, J 7.1 Hz), 1.85-2.05 (6H, m), 2.20-2.42 (3H, m), 3.42 (2H,s), 3.52 (1H, multiplet centre (mc)), 3.77 (2H, t, J 7.1 Hz), 4.10-4.16(1H, m), 4.18 (1H, d, J 8.0 Hz), 4.94 (1H, q, J 6.6 Hz), 6.99-7.01 (2H,s), 7.16 (2H, s), 7.21-7.25 (3H, m), 7.65 (1H, s); m/z (ES+) 572 (M⁺+H,100%).

EXAMPLE 128-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane

A mixture of(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde(see Example 45 in WO 00/56727) and2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane (Description 18) was reactedand purified according to the procedure described in Example 6 to givethe title compound.

¹H NMR (360 MHz, CDCl₃): δ 1.16 (6H, s), 1.35 (3H, d, J 6.6 Hz),1.38-1.61 (5H, m), 1.71 (4H, br s), 1.86-2.02 (5H, m), 2.15-2.22 (2H,m), 2.31-2.48 (2H, m), 3.50 (1H, br t), 4.08-4.15 (1H, m), 4.17 (1H, d,J 8.3 Hz), 4.93 (1H, q, J 6.6 Hz), 6.98-7.00 (2H, m), 7.16 (2H, s) 7.20(3H, br s), 7.65 (1H, s); m/z (ES+) 600 (M⁺+H, 100%).

EXAMPLE 138-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1-oxa-3-aza-spiro[4.5]decane

A mixture of(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde(see Example 45 in WO 00/56727) and 1-oxa-8-aza-spiro[4.5]decane(Description 17) was reacted and purified according to the proceduredescribed in Example 6 to give the title compound.

¹H NMR (360 MHz, CDCl₃): δ 1.35 (3H, d, J 6.6 Hz), 1.46-1.66 (8H, m),1.84 (2H, qn), 1.90-2.32 (6H, m), 2.37 (2H, t, J 7.1 Hz), 3.53 (1H, brt), 3.73 (2H, t, J 7.1 Hz), 4.13 (1H, dd, J 11.7, 3.4 Hz), 4.18 (1H, d,8.2 Hz), 4.94 (1H, q, J 6.6 Hz), 6.96-7.01 (2H, m), 7.16 (2H, s), 7.21(3H, br s), 7.65 (1H, s); m/z (ES+) 572 (M⁺+H, 100%)

EXAMPLE 148-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane

A mixture of(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran)-4-aldehyde(see Example 45 in WO 00/56727) and1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane (Bioorg. and Med. Chem. Lett.2002, 12, 1759) was reacted and purified according to the proceduredescribed in Example 6 to give the title product.

¹H NMR (360 MHz, CDCl₃): δ 1.03 (6H, s), 1.15-1.28 (2H, m), 1.35 (3H, d,J 6.6 Hz), 1.38-1.49 (2H, m), 1.50-1.59 (3H, m), 1.74 (2H, t, J 7.1 Hz),1.86-2.05 (4H, m), 2.38 (1H, br t), 2.51-2.58 (1H, m), 2.61-2.68 (1H,m), 3.52 (1H, br t), 3.73 (2H, t, J 7.1 Hz), 4.13-4.19 (2H, m), 4.93(1H, q, J 6.6 Hz), 6.98-7.01 (2H, m), 7.16 (2H, s) 7.22 (3H, br s), 7.65(1H, s); m/z (ES+) 600 (M⁺+H, 100%).

EXAMPLE 158-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-one

Dess-Martin periodinane (0.6 g, 1.4 mmol) was added to a solution of(4S)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol(Example 3; 0.85 g, 1.4 mmol) in dichloromethane (20 ml). The mixturewas stirred at room temperature for 4 hours then quenched by addition ofsaturated sodium hydrogen carbonate. After 30 minutes the mixture waspartitioned between water and dichloromethane. The organic extracts weredried and concentrated. The residue was chromatographed on silica geleluting with 2% methanol/dichloromethane to give the title compound (510mg, 60%).

¹H NMR (400 MHz, CDCl₃): δ 7.67 (1H, s), 7.17 (2H, s), 6.99-6.91 (4H,m), 4.96 (1H, q, J 6.5 Hz), 4.15-4.10 (2H, m), 3.96-3.90 (4H, m), 3.50(1H, dt, J 2, 12.1 Hz), 2.64-2.62 (1H, m), 2.52-2.49 (1H, m), 2.38 (1H,dd, J 8.4, 10.9 Hz), 2.02-1.87 (5H, m), 1.76-1.66 (3H, m), 1.45-1.39(3H, m), 1.37 (3H, d, J 6.6 Hz).

EXAMPLE 16(4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-2-oxa-4-methyl-8-aza-spiro[4.5]decan-4-ol

Methyl magnesium chloride (3.0M solution in tetrahydrofuran, 90 μl) wasadded to a solution of8-[(2R,3R,4R)-2-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-one(Example 15; 100 mg, 0.16 mmol) stirring in tetrahydrofuran (2 ml) atroom temperature. After 2 hours the reaction was quenched by addition ofsaturated ammonium chloride. The mixture was partitioned between ethylacetate and water. The organic extracts were separated, dried andconcentrated. The residue was chromatographed on silica gel eluting withdichloromethane/methanol/ammonia mixtures to give the title compound (66mg, 65%).

¹H NMR (400 MHz, CDCl₃): δ 7.67 (1H, s), 7.17 (2H, s), 7.03-6.89 (4H,m), 4.95 (1H, q, J 6.6 Hz), 4.13 (2H, m), 3.82 (1H, dd, J 5.9, 8.5 Hz),3.68-3.61 (3H, m), 3.54-3.51 (1H, m), 2.69-2.53 (2H, m), 2.39 (1H, td, J2.9, 10.9 Hz), 2.01-1.88 (5H, m), 1.62-1.41 (5H, m), 1.37 (3H, d, J 6.6Hz), 1.36-1.35 (1H, m), 1.15 (3H, s); m/z (ES+) 620 (M+H)⁺.

EXAMPLE 17(4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-4-ethynyl-8-aza-spiro[4.5]decan-4-ol

Ethynyl magnesium bromide (0.5M solution in tetrahydrofuran, 0.5 mL) wasadded to a solution of8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-one(Example 15) (100 mg, 0.16 mmol) stirring in tetrahydrofuran (2 ml) atroom temp. After 2 hours the reaction was quenched by addition ofsaturated ammonium chloride. The mixture was partitioned between ethylacetate and water. The organic extracts were separated, dried, andconcentrated. The residue was purified by chromatography on silica geleluting with dichloromethane/methanol/ammonia mixtures to give the titlecompound (51 mg, 49%).

¹H NMR (400 MHz, CDCl₃): δ 7.67 (1H, s), 7.26 (2H, s), 7.17-6.90 (4H,m), 4.95 (1H, q, J 6.6 Hz), 4.15-4.10 (2H, m), 3.97-3.95 (1H, m),3.90-3.84 (2H, m), 3.62-3.48 (2H, m), 2.69-2.57 (3H, m), 2.45-2.36 (1H,m), 2.08-1.39 (11H, m), 1.37 (3H, d, J 6.6 Hz); m/z (ES+) 630 (M+H)⁺.

EXAMPLE 18(8S)-2-[((2R,3R,4R)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-phenyl)-tetrahydro-2H-pyran-4-yl)methyl]-6-oxa-2-azaspiro[3.4]octan-8-ol

(2R,3R,4R)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-phenyltetrahydro-2H-pyran-4-carbaldehyde(WO 00/56727) (760 mg, 1.7 mmol) and 6-oxa-2-azaspiro[3.4]octan-8-ol(Description 19) (214 mg, 1.7 mmol) were dissolved in 1,2-dichloroethane(20 mL) and sodium triacetoxyborohydride (636 mg, 3 mmol) was added. Thesuspension formed was stirred at ambient temperature for 16 hrs thenquenched with 1N sodium hydroxide solution (50 mL). The biphasic mixtureformed was extracted with dichloromethane (2×50 mL), and the extractswere dried (MgSO₄) then concentrated to give a gum. The residue waspurified by silica chromatography to give a mixture of the twodiastereomers, which could be separated by chiral HPLC (Cyclobond II,7.5% EtOH/hexane) to give isomer A (for isomer B, see Example 19):Isomer A: ¹H NMR (400 MHz, CDCl₃): δ 7.65 (1H, s), 7.24-7.21 (3H, m),7.15 (2H, s), 7.03-6.99 (2H, m), 4.93 (1H, q, J 6.6 Hz), 4.21 (1H, dd, J2.9, 4.6 Hz), 4.17 (1H, d, J 8.4 Hz), 4.12 (1H, ddd, J 1.7, 4.6, 11.7Hz) 3.84 (1H, dd, J 4.6, 9.9 Hz), 3.76 (2H, s), 3.62 (1H, dd, J 2.8, 9.0Hz), 3.50 (1H, dt, J 2.4, 12.3 Hz), 3.37 (1H, d, J 7.4 Hz), 3.03 (1H, d,J 6.9 Hz), 2.80 (2H, dd, J 7.4, 14.8 Hz), 2.41 (1H, dd J 8.0, 11.3 Hz),2.16 (1H, dd, J 9.5, 12.3 Hz), 2.07 (1H, dd, J 3.3, 11.8 Hz) 1.85-1.75(2H, m), 1.63 (1H, br m), 1.52-1.41 (1H, m), 1.35 (3H, d, J 6.6 Hz); m/z(ES⁺) 560 (M+H).

EXAMPLE 19(8R)-2-[((2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-6-oxa-2-azaspiro[3.4]octan-8-ol

This product was the second peak to elute from the prep HPLC rundescribed in Example 18.

Isomer B: ¹H NMR (360 MHz, CDCl₃): δ 7.65 (1H, s), 7.27-7.12 (5H, m),7.01-6.99 (2H, m), 4.93 (1H q, J 6.6 Hz), 4.23 (1H, dd, J 3.2, 5.3 Hz),4.17 (1H, dd, J 9.3 Hz), 4.12 (1H, ddd, J 2.0, 7.3, 11.8 Hz), 3.84 (1H,dd, J 4.6, 9.8 Hz), 3.75 (2H, s), 3.61 (1H, dd, J 3.1, 9.8 Hz), 3.50(1H, dt, J 2.4, 12.3 Hz), 3.42 (1H, d, J 7.3 Hz), 3.04 (1H, d, J 6.8Hz), 2.87 (1H, d, J 6.8 Hz), 2.72 (1H, d, J 6.8 Hz), 2.41 (1H, dd, J8.5, 11 Hz), 2.17 (1H, dd, J 9.2, 12.0 Hz), 2.07 (1H, dd, J 3.6, 12.6Hz), 1.86-1.76 (3H, m), 1.52-1.41 (1H, m), 1.35 (3H, d, J 6.6 Hz); m/z(ES+) 560 (M+H).

EXAMPLE 20(4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol

This product was prepared according to the procedure described inExample 2 using(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-carbaldehyde(WO 0056727) and 4-hydroxy-1-oxa-8-azaspiro[4.5]decane (Description 20).

¹H NMR (500 MHz, CDCl₃): δ 1.35 (3H, d, J 6.6 Hz), 1.38-1.55 (2H, m),1.6-1.98 (4H, m), 2.00-2.25 (4H, m), 2.38 (1H, dd, J 11.2, 8.4 Hz),2.39-2.7 (2H, m), 3.53 (1H, t, J 12.0 Hz), 3.72-3.76 (1H, m), 3.89 (1H,multiplet centre (mc)), 4.13 (1H, dd, J 11.8, 3.4 Hz), 4.20 (1H, d, J8.3 Hz), 4.94 (1H, q, J 6.5 Hz), 6.99-7.00 (2H, m), 7.16 (2H, s),7.21-7.22 (3H, m), 7.65 (1H, s); m/z (ES⁺) 588 (M⁺+1, 100%).

EXAMPLE 21(4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-4-ol

This product was prepared according to the procedure described inExample 6 using(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde(Description 11) and 4-hydroxy-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane(Description 21).

¹H NMR (400 MHz, MeOD): δ 1.12 (3H, s), 1.24 (3H, s), 1.36 (3H, d, J 6.6Hz), 1.39-1.44 (2H, m), 1.56-1.78 (4H, m), 1.82-2.06 (4H, m), 2.37 (1H,t, J 9.1 Hz), 2.39-2.56 (2H, m), 3.44 (1H, s), 3.45-3.58 (3H, m),4.10-4.14 (2H, m), 4.95 (1H, q, J 6.6 Hz), 6.91-6.99 (4H, m), 7.17 (1H,s), 7.67 (1H, s); m/z (ES⁺) 634 (M⁺+1, 100%).

EXAMPLE 22(4R*)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-1-oxa-3-spiro[4.5]decan-4-ol

This compound was prepared from the reaction of the compounds ofDescription 11 and 20 following the procedure described in Example 6.The product was purified by chromatography on silica to give a mixtureof two diastereomers, which were separated by chiral HPLC (Cyclobond II,7.5% EtOH/hexane) to give isomer A:

¹H NMR (500 MHz, CDCl₃): δ 7.67 (1H, s), 7.17 (2H, s), 6.98-6.90 (4H,m), 4.95 (1H, q, J 6.4 Hz), 4.12 (2H, dd, J 2.1, 8.3 Hz), 3.93-3.89 (2H,m), 3.78-3.74 (1H, m), 3.52 (1H, dd, J 12.1, 12.1 Hz), 2.38 (2H, t, J8.7 Hz), 2.29-2.19 (3H, m), 2.01 (2H, m), 1.93 (2H, m), 1.85 (1H, m),1.71 (1H, m), 1.41 (3H, s), 1.36 (3H, d, J 6.6 Hz); m/z (ES+) 606.

EXAMPLE 23(4S*)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-Bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-yl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol

This compound was prepared from the reaction of the compounds ofDescription 11 and 20 following the procedure described in Example 6.The product was purified by chromatography on silica to give a mixtureof two isomers, which were separated by chiral HPLC (Chiralpak AD, 2%EtOH in hexane) to give isomer A (see Example 22) and isomer B:

¹H NMR (500 MHz, CDCl₃): δ 7.67 (1H, s), 7.17 (2H, s), 6.98-6.90 (4H,m), 4.97-4.93 (1H, q, J 6.6 Hz), 4.12 (2H, dd, J 2.6, 8.4 Hz), 3.93-3.87(2H, m), 3.79-3.73 (1H, m), 3.51 (1H, dd, J 10, 10 Hz), 2.47 (1H, m),2.38 (1H, t, J 9.6 Hz), 2.26-2.19 (3H, m), 2.03-1.93 (5H, m), 1.88-1.82(1H, m), 1.40-1.34 (6H, m); m/z (ES+) 606.

EXAMPLE 24(4R)-8-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2-pyran-4-yl)methyl]-4-methoxy-2-oxa-3-azaspiro[4-5]decane

To a solution of(4R)-8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-phenyltetrahydro-2H-pyranyl]methyl-2-oxa-8-azaspiro[4.5]decan-4-ol(Example 2) (100 mg, 0.17 mmol) in anhydrous DMF (1 mL) was added a 60%dispersion of sodium hydride in mineral oil (40 mg) under ice cooling.After 15 min of stirring at 0° C. methyl iodide (31 mg) was added andthe mixture was stirred at r.t. for 18 h, before it was diluted withwater and extracted with ethyl acetate. The combined organic phases werewashed with brine, dried over magnesium sulfate, filtered andconcentrated in vacuo to give the crude product as colourless oil, whichwas then purified by flash chromatography on silica using 3-5% methanolin dichloromethane as eluant. The desired product was obtained ascolourless viscous oil (76%).

¹H NMR (360 MHz, CDCl₃): δ 7.65 (1H, s), 7.22 (3H, m), 7.16 (2H, s),7.01 (2H, m), 4.94 (1H, q, J 6.6 Hz), 4.18 (1H, d, J 8.4 Hz), 4.13 (1H,dd, J 3.3, 15 Hz), 3.90 (1H, dd, J 4.4, 9.8 Hz), 3.77 (1H, dd, J 2.0,9.9 Hz), 3.56-3.48 (3H, m), 3.38-3.34 (1H, m), 3.25 (3H, s), 2.41-2.35(2H, m), 2.19-2.06 (2H, m), 2.06-1.87 (7H, m), 1.79-1.73 (1H, m),1.47-1.39 (4H, m), 1.35 (3H, d, J 6.6 Hz); m/z (ES+) 602.

EXAMPLE 25(4R)-8-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)tetrahydro-2-H-pyran-4-yl)methyl]-4-methoxy-2-oxa-8-azaspiro[4.5]decane

This compound was prepared from the compound of Example 4 following theprocedure described in Example 24.

¹H NMR (360 MHz, CDCl₃): δ 7.67 (1H, s), 7.17 (2H, s), 7.00-6.92 (4H,m), 4.95 (1H, q, J 6.6 Hz), 4.16-4.09 (2H, m), 3.90 (1H, dd, J 4.4, 9.9Hz), 3.77 (1H, dd, J 2.1, 9.9 Hz), 3.56-3.48 (3H, m), 3.37 (1H, dd, J2.1, 4.3 Hz), 3.26 (3H, s), 2.41-2.33 (2H, m), 2.16-2.07 (2H, m),2.02-1.84 (5H, m), 1.79-1.71 (1H, m), 1.49-1.39 (2H, m), 1.36 (3H, d, J6.6 Hz); m/z (ES+) 620, 362.

EXAMPLE 268-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-1-oxa-3-azaspiro[4.5]decan-3-ol

To a solution of(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-carbaldehyde(WO 00/56727) (0.97 g, 2.71 mmol) and triethylamine (0.72 mL, 5.17 mmol)in 1,2-dichloroethane (15 mL) was added 1-oxa-8-aza[4.5]decan-3-oltrifluoroacetate (Description 22) (775 mg), followed by sodiumtriacetoxyborohydride (630 mg, 3 mmol). The reaction mixture was stirredfor 2 h at room temperature, then treated with dilute sodium hydroxidesolution and extracted with dichloromethane. The combined organic phaseswere washed with brine, dried over magnesium sulfate, filtered andconcentrated to give the crude product as a light brown oil. Flashchromatography on a column of silica gel with a gradient solvent systemof 5-10% methanol in dichloromethane afforded the title compound as amixture of epimers (53%, 0.85 g).

¹H NMR (360 MHz, CDCl₃): δ 7.66 (1H, s), 7.22 (3H, s), 7.16 (2H, s),7.00 (2H, m), 4.94 (1H, q, J 6.6 Hz), 4.43 (1H, br s), 4.20 (1H, d, J8.2 Hz), 4.13 (1H, dd, J 3.3, 11.9 Hz), 3.82 (1H, dd, J 4.2, 9.9 Hz),3.72 (1H, d, J 10.1 Hz), 3.54 (1H, dd, J 12, 12 Hz), 2.59-1.41 (ca. 20H,methylene envelope), 1.24 (3H, d, J 6.6 Hz); m/z (ES+) 588.

EXAMPLE 278-[((2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-1-oxa-8-azaspiro[4.5]decan-3-one

This compound was prepared from the compound of Example 26 following theprocedure described in Example 15.

¹H NMR (360 MHz, CDCl₃): δ 7.65 (1H, s), 7.23-7.19 (3H, m), 7.17 (2H,s), 7.09-6.97 (2H, m), 4.94 (1H, q, J 6.5 Hz), 4.18 (1H, d, J 8.3 Hz),4.13 (1H, dd, J 4.2, 11.7 Hz), 3.92 (2H, s), 3.53 (1H, t, J 11.1 Hz),2.49-2.42 (1H, m), 2.39 (1H, dd, J 8.4, 10.8 Hz), 2.31-2.17 (2H, m),2.05 (2H, dd, J 10.2, 12.6 Hz), 2.00-1.93 (3H, m), 1.76-1.68 (2H, m),1.67-1.58 (2H, m), 1.48-1.38 (1H, m), 1.36 (3H, d, J 6.6 Hz); m/z (ES+)586.

EXAMPLE 28 (2R or S,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)tetrahydro-N-(phenylmethyl)-2-furanmethanamine

A solution of (2RS,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1,2,5-pentanetriol1-(4-methylbenzenesulfonate) 5-methanesulfonate (3:1 mixture of alcoholdiastereoisomers; Description 27; 0.48 g, 0.63 mmol) andbenzenemethanamine (0.69 mL, 6.3 mmol) in methanol (10 mL) was placed ina sealed tube and heated in a microwave oven at 140° C. for 10 minutes.The mixture was cooled and the solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate (20 mL), washedwith saturated aqueous potassium carbonate (20 mL) and brine (20 mL),dried (Na₂SO₄), and the solvent was evaporated under reduced pressure.The residue was purified by preparative thin layer chromatography onsilica gel, eluting with EtOAc/MeOH/NH₃(Aq.) (98:2:0.2), to give thetitle compound (single diastereoisomer) as a colorless oil (0.12 g,31%).

¹H NMR (500 MHz, CD₃OD) δ 7.71 (1H, s), 7.31-7.06 (12H, m), 4.99 (1H, q,J 6.5 Hz), 4.34 (1H, d, J 8.5 Hz), 4.10 (1H, m), 3.94 (1H, m), 3.63 (3H,m), 3.53 (1H, m), 2.41 (3H, m), 2.29 (1H, m), 1.92 (1H, m), 1.71 (3H,m), 1.51 (1H, m), 1.36 (1H, m), 1.32 (3H, d, J 6.6 Hz); m/z (ES⁺) 608(M+1).

EXAMPLE 29 (2S or R,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)tetrahydro-N-(phenylmethyl)-2-furanmethanamine

The title compound (single diastereoisomer) was prepared from (2RS,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1,2,5-pentanetriol1-(4-methylbenzenesulfonate) 5-methanesulfonate (1:3 mixture of alcoholdiastereoisomers; Description 28) according to the method of Example 28.

¹H NMR (500 MHz, CD₃OD): δ 7.71 (1H, s), 7.31-7.06 (12H, m), 4.99 (1H,q, J 6.5 Hz), 4.34 (1H, d, J 8.5 Hz), 4.10 (1H, m), 3.78 (1H, m), 3.63(2H, ABX), 3.60 (1H, dt, J 2.0, 11.8 Hz), 3.45 (1H, m), 2.53 (1H, dd, J3.7, 12.0 Hz), 2.46 (1H, dd, J 8.4, 12.0 Hz), 2.39 (1H, dd, J 8.3, 11.8Hz), 2.27 (1H, m), 1.80 (1H, m), 1.65 (3H, m), 1.42 (2H, m), 1.32 (3H,d, J 6.6 Hz); m/z (ES⁺) 608 (M+1).

EXAMPLE 30 (2R or S,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2-pyran-4-yl)tetrahydro-2-furanmethanamine

Dried palladium hydroxide on carbon (20 mg) was added to a solution of(2R or S,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)tetrahydro-N-(phenylmethyl)-2-furanmethanamine(Example 28; 0.12 g, 0.20 mmol) in ethanol (3 mL) and the mixture wasstirred under hydrogen (1 Atmosphere) for 12 hours. The mixture wasfiltered through Celite™ and the solvent was evaporated under reducedpressure. The residue was purified by preparative thin layerchromatography on silica gel, eluting with EtOAc/MeOH/NH₃(Aq.) (90:10:1)then by preparative HPLC (Supelsosil™ ABZ+PLUS 100×21.2 mm i.d.;gradient 0.1% TFA-H₂O/45% MeCN to 0.1% TFA-H₂O/55% MeCN over 10 min; 20mL/min; 210 nm; 400 μl injections of a 20 mg/mL solution in MeCN), togive the title compound (single diastereoisomer) as a colorless oil(0.30 mg, 29%).

¹H NMR (500 MHz, CD₃OD) δ 7.71 (1H, s), 7.31 (2H, m), 7.17 (3H, m), 7.09(2H, m), 4.99 (1H, q, J 6.5 Hz), 4.36 (1H, d, J 8.1 Hz), 4.14 (1H, m),3.83 (1H, m), 3.63 (1H, dt, J 2.3, 11.0 Hz), 3.57 (1H, m), 2.53 (1H, m),2.43 (2H, m), 2.32 (1H, m), 1.92 (1H, m), 1.73 (3H, m), 1.53 (1H, m),1.40 (1H, m), 1.32 (3H, d, J 6.6 Hz); m/z (S+) 518 (M+1), 260(M+1-C₁₀H₈F₆O).

EXAMPLE 31 (2S or R,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-N,N-diethyltetrahydro-2-furanmethanamine

The title compound was prepared from (2S or R,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)tetrahydro-N-(phenylmethyl)-2-furanmethanamine(Example 29) according to the method of Example 30.

¹H NMR (500 MHz, CD₃OD) δ 7.71 (1H, s), 7.31 (2H, s), 7.17 (3H, m), 7.09(2H, m), 4.99 (1H, q, J 6.5 Hz), 4.36 (1H, d, J 8.1 Hz), 4.14 (1H, m),3.63 (1H, m), 3.45 (1H, dt, J 2.3, 11.0 Hz), 3.30 (1H, m), 2.70-2.53(5H, m), 2.41 (1H, dd, J 8.1, 12.0 Hz), 2.33 (1H, m), 1.88 (1H, m), 1.70(3H, m), 1.53 (1H, m), 1.40 (1H, m), 1.32 (3H, d, J 6.6 Hz), 1.02 (6H,t, J 7.1 Hz); m/z (ES⁺) 574 (M+1).

EXAMPLE 32 (3R orS)-3-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)thiomorpholine;and (3S orR)-3-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)thiomorpholine

Methanesulfonyl chloride (0.12 mL, 0.17 g, 1.5 mmol) was added dropwiseto a stirred, cooled (−10° C.) solution of (2R,3R,4R,αR orS)-α-{[(2-hydroxyethyl)thio]methyl}-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-methanoland (2R,3R,4R,αS orR)-α-{[(2-hydroxyethyl)thio]methyl}-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-methanol(Description 30, 1:1 mixture of diastereoisomers; 269 mg, 0.5 mmol) andtriethylamine (0.28 mL, 0.20 g, 2 mmol) in dichloromethane (5 mL) andthe mixture was stirred at −10° C. for 10 minutes. Water (20 mL) wasadded and the mixture was extracted with dichloromethane (3×20 mL). Thecombined organic fractions were washed with aqueous citric acid (10%,2×20 mL), saturated aqueous sodium hydrogen carbonate/water (1:1, 2×20mL) and brine (20 mL), dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was dissolved in methanolic ammonia(7M, 5 mL), placed in a sealed tube and heated in a microwave oven at60° C. for 10 minutes. The mixture was cooled and the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(aq.)(99:1:0.1 increasing to 96:4:0.4), to give the title compound (1:1mixture of thiomorpholine epimers) as a colorless foam (81 mg, 31%).

¹H NMR (500 MHz, CD₃OD) δ 7.71, 7.70 (1H, each s), 7.32-7.12 (7H, m),4.99 (1H, m), 4.39, 4.32 (1H, each d, J 8.4 Hz), 4.08 (1H, m), 3.58 (1H,m), 3.13-2.36 (8H, m), 2.08 (1H, m), 1.82-1.55 (2H, m), and 1.32, 1.31(3H, each d, J 6.6 Hz); m/z (ES⁺) 520 (M+1) and 262 (M+1-C₁₀H₈F₆O).

EXAMPLE 33(2S)-2-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-1-methylazetidine

(1R)-1-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1,3-propanedioldimethylsulfonate (Description 35; 0.25 g, 0.39 mmol) was dissolved inmethylamine (2.0M in methanol, 4 mL) and heated at 140° C. for 10minutes in a sealed tube in a Smith microwave reactor. The mixture wascooled and the solvent was evaporated under reduced pressure. Saturatedaqueous potassium carbonate (50 mL) was added and the mixture wasextracted with ethyl acetate (3×50 mL). The combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by preparative thin layerchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(100:10:1), to give the title compound as a pale yellow solid (20 mg,10%).

¹H NMR (500 MHz, CD₃OD) δ 1.31 (3H, d, J 6.6 Hz), 1.58 (1H, app dq,),1.75 (1H, m), 1.81 (1H, m), 2.00 (1H, m), 2.10 (1H, m), 2.30 (1H, dd, J8.2, 11.6 Hz), 2.59 (1H, q, J 9.4 Hz), 2.80 (1H, m), 3.22 (1H, m), 3.64(1H, dd, J 9.7, 12.0 Hz), 4.14 (1H, m), 4.34 (1H, d, J 8.2 Hz), 4.99(1H, q, J 6.6 Hz), 7.07-7.09 (2H, m), 7.19-7.24 (3H, m), 7.31 (2H, s),7.71 (1H, s); m/z (ES⁺) 488 (M+1) and 230 (M+1-C₁₀H₈F₆₀).

EXAMPLE 34(2R)-2-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-1-methylazetidine

Prepared from(1S)-1-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1,3-propanedioldimethylsulfonate (Description 36) according to the method of Example33.

¹H NMR (500 MHz, CD₃OD) δ 1.05 (1H, m), 1.14 (1H, m), 1.31 (3H, d, J 6.6Hz), 1.42 (1H, m), 1.80 (1H, dd, J 4, 2 Hz), 2.12 (1H, m), 2.33 (3H, s),2.36 (1H, m), 2.62 (1H, m), 2.93 (1H, m), 3.14 (1H, m), 3.63 (1H, dd, J12.1, 2.1 Hz), 4.12 (1H, m), 4.42 (1H, d, J 8.5 Hz), 4.99 (1H, m),7.05-7.06 (2H, m), 7.15-7.18 (3H, m), 7.32 (2H, app. s), 7.71 (1H, s);m/z (ES⁺) 488 (M+1) and 230 (M+1-C₁₀H₈F₆O).

EXAMPLE 354-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)piperidin-4-ol

3-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1,3,5-propanetriol1,5-dimethylsulfonate Description 40; 0.13 g, 0.19 mmol) was dissolvedin methanolic ammonia (7M, 2 mL) and heated at 130° C. for 20 minutes ina sealed tube in a Smith microwave reactor. The mixture was cooled andthe solvent was evaporated under reduced pressure. The residue wasdissolved in water (25 mL) and basified with saturated aqueous potassiumcarbonate. The mixture was extracted with dichloromethane (3×30 mL). Thecombined organic fractions were dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(90:10:1), to give the title compound as a colorless oil (25 mg, 25%).

¹H NMR (500 MHz, CDCl₃) δ 7.65 (1H, s), 7.24-7.18 (3H, m), 7.16 (2H, s),7.12 (2H, m), 4.90 (1H, q, J 6.6 Hz), 4.25 (1H, d, J 7.4 Hz), 4.16 (1H,br d, J 11 Hz), 3.54 (1H, br t, J 11 Hz), 2.84-2.79 (4H, m), 2.72 (1H,s), 2.02 (1H, br t, J 11 Hz), 1.8 (1H, br s), 1.78 (1H, br d, J 11 Hz),1.64 (1H, br q, J 11 Hz), 1.56-1.51 (3H, m), 1.36 (3H, d, J 6.6 Hz),1.31 (1H, m), 1.2 (1H, br s); m/z (ES⁺) 518 (M+1) and 260(M+1-C₁₀H₈F₆O).

EXAMPLE 364-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-cyclopropylpiperidin-4-ol

Prepared from3-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyranyl)-1,3,5-propanetriol1,5-dimethylsulfonate (Description 40) and cyclopropylamine according tothe method of Example 33.

¹H NMR (500 MHz, CD₃OD) δ 7.69 (1H, s), 7.27 (2H, s), 7.16-7.10 (5H, m),4.92 (1H, q, J 6.6 Hz), 4.25 (1H, d, J 8.1 Hz), 4.10 (1H, br d, J 12Hz), 3.60 (1H, br t, J 12 Hz), 2.80 (1H, dd, J 11.1, 8.1 Hz), 2.65 (1H,m), 2.52-2.44 (2H, m), 2.34 (1H, m), 2.08 (1H, br t, J 12 Hz), 1.78 (1H,br d, J 12 Hz), 1.69 (1H, br q, J 12 Hz), 1.56 (1H, m), 1.45 (1H, m),1.34 (1H, m), 1.32 (3H, d, J 6.6 Hz), 1.12 (2H, m), 0.41 (2H, m), 0.30(2H, m); m/z (ES+) 558 (M+1) and 300 (M+1-C₁₀H₈F₆O).

EXAMPLE 374-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-(1-methylethyl)piperidin-4-ol

Prepared from3-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-1,3,5-propanetriol1,5-dimethylsulfonate (Description 40) and isopropylamine according tothe method of Example 33.

¹H NMR (500 MHz, CD₃OD) δ 7.70 (1H, s), 7.27 (2H, s), 7.18-7.11 (5H, m),4.93 (1H, q, J 6.6 Hz), 4.27 (1H, d, J 8.1 Hz), 4.11 (1H, br d, J 12Hz), 3.61 (1H, br t, J 12 Hz), 2.86 (1H, m), 2.80 (1H, dd, J 11.1, 8.1Hz), 2.76-2.55 (4H, m), 2.12 (1H, br t, J 12 Hz), 1.79 (1H, br d, J 12Hz), 1.70 (1H, br q, J 12 Hz), 1.60 (1H, m), 1.47 (1H, m), 1.32 (3H, d,J 6.6 Hz), 1.24 (2H, m), 1.09 (3H, d, J 6.5 Hz), 1.08 (3H, d, J 6.5 Hz);m/z (ES⁺) 560 (M+1).

EXAMPLE 38 (α[R orS)-α-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-1-piperidineethanolHydrochloride

A mixture of(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-4-[(2Ror S)-oxiranyl]-3-phenyl-2H-pyran (Description 41, Isomer A; 70 mg, 0.15mmol) and piperidine (45 μL, 39 mg, 0.46 mmol) in methanol (5 mL) wasplaced in a sealed tube and heated in a microwave oven at 130° C. for 20minutes. The mixture was cooled and the solvent was evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel, eluting with EtOAc then CH₂Cl₂/MeOH/NH₃(Aq.) (95:5:0.5),then by column chromatography on silica gel, eluting with CH₂Cl₂/MeOH(90:10) to give (αR orS)-α-((2R,3R,4R)-((1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-piperidineethanolas a solid (28 mg, 34%). The solid was dissolved in diethyl ether andethereal hydrogen chloride (1M, 0.2 mL) was added. The solid wascollected and dried in vacuo to give the title compound as a colorlesssolid.

¹H NMR (500 MHz, CDCl₃) δ 11.0 (1H, s), 7.66 (1H, s), 7.24 (3H, m), 7.18(2H, s), 7.03 (2H, m), 4.95 (1H, q, J 6.6 Hz), 4.24 (1H, d, J 8.5 Hz),4.17 (1H, br d, J 11 Hz), 3.76 (1H, br d, J 11 Hz), 3.50 (1H, br t, J 11Hz), 3.43 (1H, br d, J 11 Hz), 3.31 (1H, br d, J 11 Hz), 2.94 (1H, br t,J 11 Hz), 2.87 (1H, dd, J 11.2, 8.5 Hz), 2.55 (1H, br q, J 11 Hz),2.40-2.10 (4H, m), 1.95-1.05 (6H, m), 1.35 (3H, d, J 6.6 Hz), 1.32 (1H,m); m/z (ES⁺) 546 (M+1) and 288 (M+1-C₁₀H₈F₆O).

EXAMPLE 39 (αS orR)-α-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-1-piperidineethanolHydrochloride

Prepared from(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-4-[(2Sor R)-oxiranyl]-3-phenyl-2H-pyran (Description 41, Isomer B) andpiperidine according to the method of Example 38.

¹H NMR (400 MHz, CDCl₃) δ 11.18 (1H, s), 7.65 (1H, s), 7.25 (3H, m),7.12 (2H, s), 7.05 (2H, m), 4.92 (1H, q, J 6.6 Hz), 4.20 (1H, d, J 8.1Hz), 4.18 (1H, br d, J 11 Hz), 3.85 (1H, br d, J 11 Hz), 3.55 (1H, br t,J 11 Hz), 3.40(1H, br d, J 11 Hz), 3.06 (1H, br d, J 11 Hz), 2.76-2.58(3H, m), 2.48 (1H, dd, J 12.2, 8.1 Hz), 2.29-1.45 (11H, m), 1.35 (3H, d,J 6.6 Hz); m/z (ES⁺) 546 (M+1) and 288 (M+1-C₁₀H₈F₆O).

EXAMPLE 40 (αR orS,2R,3R,4R)-2-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-α-[(dimethylamino)methyl]-3-phenyl-2H-pyran-4-methanolHydrochloride

Prepared from(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-4-[(2Ror S)-oxiranyl]-3-phenyl-2H-pyran (Description 41, Isomer A) anddimethylamine according to the method of Example 38.

¹H NMR (500 MHz, CDCl₃) δ 11.3 (1H, br s), 7.66 (1H, s), 7.24-7.26 (3H,m), 7.19 (2H, s), 7.04-7.05 (2H, m), 4.96 (1H, q, J 6.6 Hz), 4.26 (1H,d, J 8.4 Hz), 4.18 (1H, dd, J 11.7, 3.3 Hz), 3.70 (1H, br d, J 9.7 Hz),3.52 (1H, br t, J 11.8 Hz), 3.09 (1H, br t, J 12.1 Hz), 2.86 (1H, dd, J11.0, 8.6 Hz), 2.64 (6H, br s), 2.43 (1H, br d, J 12.3 Hz), 1.89 (1H,m), 1.77 (1H, m), 1.60 (1H, br d, J 12.8 Hz), 1.36 (3H, d, J 6.6 Hz);m/z (ES⁺) 506 (M+1) and 248 (M+1-C₁₀H₈F₆O).

EXAMPLE 41 1,1-Dimethylethyl(2R or S)-2-[(R orS)-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)hydroxymethyl]-1-pyrrolidinecarboxylate(Isomers A and B)

sec-Butyllithium (1.4M in hexanes, 1.6 mL, 2.24 mmol) was added slowlyto a stirred, cooled (−78° C.) solution of 1,1-dimethylethyl1-pyrrolidinecarboxylate (0.4 mL, 2.24 mmol) andN,N,N′,N′-tetramethyl-1,2-ethanediamine (0.3 mL, 2.02 mmol) in diethylether (4.5 mL). The mixture was stirred at −78° C. for 3 hours, then(2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxaldehyde(WO 00/56727A1; 0.5 g, 1.12 mmol) in diethyl ether (1 mL) was addeddropwise. The mixture was stirred at −78° C. for 30 minutes, then warmedto room temperature. Water (2 mL) was added slowly, then ethyl acetate(10 mL). The layers were separated and the organic layer was washed withbrine (5 mL). The combined aqueous layers were extracted with ethylacetate (10 mL). The combined organic layers were dried (Na₂SO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby column chromatography on silica gel, eluting with hexane/EtOAc (85:15increasing to 75:25), to give: 1,1-dimethylethyl(2R or S)-2-[(R orS)-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)hydroxymethyl]-1-pyrrolidinecarboxylate(Isomer A; Single diastereoisomer; Stereochemistry unassigned) as acolorless oil (0.25 g, 36%); ¹H NMR (500 MHz, CDCl₃) δ 7.67 (1H, s),7.21 (5H, m), 7.20 (2H, s), 7.03 (2H, m), 4.95 (1H, q, J 6.5 Hz), 4.28(1H, d, J 8.3 Hz), 4.20 (1H, m), 3.87 (1H, m), 3.53 (1H, dt, J 1.6, 10.8Hz), 3.33 (2H, m), 3.11 (1H, m), 2.98 (1H, dd, J 8.3, 11.3 Hz), 2.92(1H, m), 2.04 (1H, m), 1.75 (3H, m), 1.60 (1H, m), 1.44 (11H, m), 1.35(3H, d, J 6.6 Hz); and 1,1-dimethylethyl(2R or S)-2-[(R orS)-((2R,3R,4R)-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)hydroxymethyl]-1-pyrrolidinecarboxylate(Isomer B; Single diastereoisomer; Stereochemistry unassigned) as acolorless oil (0.26 g, 38%); ¹H NMR (500 MHz, CDCl₃) δ 7.67 (1H, s),7.21 (5H, m), 7.20 (2H, s), 7.03 (2H, m), 4.95 (1H, q, J 6.5 Hz), 4.28(1H, d, J 8.3 Hz), 4.20 (1H, m), 4.00-2.81 (5H, m), 1.93 (2H, m), 1.70(3H, m), 1.44 (11H, m), 1.35 (3H, d, J 6.6 Hz).

EXAMPLE 42 (1R or S, 7aR orS)-1-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one(Isomer A)

Sodium hydride (60% dispersion in mineral oil, 15 mg, 0.36 mmol) wasadded to a solution of 1,1-dimethylethyl(2R or S)-2-[(R orS)-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)hydroxymethyl]-1-pyrrolidinecarboxylate(Example 41, Isomer A; 75 mg, 0.12 mmol) in tetrahydrofuran (2 mL) andthe mixture was stirred at room temperature for 15 hours. Water (2 mL)was added slowly, then ethyl acetate (10 mL). The layers were separatedand the organic layer was washed with brine (5 mL). The combined aqueouslayers were extracted with ethyl acetate (10 mL). The combined organiclayers were dried (Na₂SO₄) and the solvent was evaporated under reducedpressure. The residue was purified by column chromatography on silicagel, eluting with hexane/EtOAc (80:20 increasing to 60:40), to give thetitle compound (Single diastereoisomer; Stereochemistry unassigned) as acolorless foam (54 mg, 82%).

¹H NMR (500 MHz, CDCl₃) δ 7.67 (1H, s), 7.26 (3H, m), 7.20 (2H, s), 7.06(2H, m), 4.95 (1H, q, J 6.5 Hz), 4.28 (1H, d, J 8.3 Hz), 4.20 (1H, dt, J11.4, 3.4 Hz), 3.96 (1H, t, J 3.5 Hz), 3.53 (2H, m), 3.34 (1H, m), 3.06(1H, m), 2.82 (1H, dd, J 8.3, 11.3 Hz), 1.93 (2H, m), 1.78 (2H, m), 1.68(2H, m), 1.35 (3H, d, J 6.6 Hz), 1.20 (1H, m).

EXAMPLE 43 (1R or S, 7aR orS)-1-((2R,3R,4R)-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one(Isomer B)

Prepared from (2R or S)-2-[(R orS)-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)hydroxymethyl]-1-pyrrolidinecarboxylate(Example 41, Isomer B) according to the method of Example 42.

¹H NMR (500 MHz, CDCl₃) δ 7.67 (1H, s), 7.30 (2H, s), 7.24 (3H, m), 7.08(2H, m), 4.98 (1H, q, J 6.5 Hz), 4.54 (1H, dd, J 6.5, 8.6 Hz), 4.42 (1H,d, J 7.2 Hz), 4.17 (1H, dt, J 11.9, 4.0 Hz), 3.60 (1H, dt, J 1.6, 10.8Hz), 3.55 (1H, m), 2.95 (2H, m), 2.62 (1H, dd, J 7.3, 9.5 Hz), 2.14 (1H,m), 1.98 (1H, m), 1.86 (1H, m), 1.78 (1H, m), 1.52 (1H, m), 1.39 (3H, d,J 6.6 Hz), 1.18 (1H, m), 1.04 (1H, m).

EXAMPLE 44 (2R,3R,4R,αR or S)-α-[(2R orS)-2-Pyrrolidinyl]-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol(Isomer B)

Lithium hydroxide (30 mg, 0.70 mmol) was added to a solution of (1R orS, 7aR orS)-1-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one(Example 43, Isomer B; 76 mg, 0.14 mmol) in tetrahydrofuran (1 mL),methanol (1 mL) and water (1 mL) and the mixture was stirred at 50° C.for 3 days. The mixture was cooled and water (5 mL) and ethyl acetate(10 mL) were added. The layers were separated and the organic layer waswashed with brine (5 mL). The combined aqueous layers were extractedwith ethyl acetate (10 mL). The combined organic layers were dried(Na₂SO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by preparative thin layer chromatography on silicagel, eluting with EtOAc/MeOH/NH₃(Aq.) (85:15:1.5), to give the titlecompound (Single diastereoisomer; Stereochemistry unassigned) as acolorless oil (50 mg, 70%).

¹H NMR (500 MHz, CD₃OD) δ 7.71 (1H, s), 7.32 (2H, s), 7.22-7.12 (5H, m),5.00 (1H, q, J 6.5 Hz), 4.39 (1H, d, J 8.6 Hz), 4.11 (1H, dt, J 11.4,3.4 Hz), 3.64 (1H, dt, J 2.4, 12.0 Hz), 2.98 (1H, dd, J 2.0, 8.2 Hz),2.90 (1H, q, J 7.8 Hz), 2.79 (2H, m), 2.70 (1H, m), 2.10 (1H, m), 1.83(1H, m), 1.73 (1H, m), 1.63 (3H, m), 1.41 (1H, m), 1.33 (3H, d, J 6.6Hz); m/z (ES⁺) 518 (M+1), 260 (M+1-C₁₀H₈F₆O).

1-14. (canceled)
 15. A compound of the formula (I):

wherein W represents:

R¹ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, fluoroC₁₋₆alkyl,fluoroC₁₋₆alkoxy, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, NO₂, CN,SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₄alkyl substituted by C₁₋₄alkoxy, wherein R^(a) andR^(b) each independently represent hydrogen or C₁₋₄alkyl; R² ishydrogen, halogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl or C₁₋₆alkoxy substitutedby C₁₋₄alkoxy; R³ is hydrogen, halogen or fluoroC₁₋₆alkyl; R⁴ ishydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, fluoroC₁₋₆alkyl,fluoroC₁₋₆alkoxy, hydroxy, NO₂, CN, SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a),CONR^(a)R^(b), C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₄alkyl substituted byC₁₋₄alkoxy, wherein R^(a) and R^(b) are as previously defined; R⁵ ishydrogen, halogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl or C₁₋₆alkoxy substitutedby C₁₋₄alkoxy; R⁶ represents hydrogen or a C₁₋₄alkyl group optionallysubstituted by a hydroxy group; R⁷ represents hydrogen, C₁₋₆alkyl,fluoroC₁₋₆alkyl, hydroxy, C₁₋₆alkoxy or hydroxyC₁₋₆alkyl; R⁸ and R⁹ eachindependently represent hydrogen, halogen, C₆alkyl, CH₂OR^(c), oxo,CO₂R^(a) or CONR^(a)R^(b) where R^(a) and R^(b) are as previouslydefined and R^(c) represents hydrogen, C₁₋₆alkyl or phenyl; andpharmaceutically acceptable salts thereof; wherein when W is

A represents an oxygen atom or a CH₂ group; B represents an oxygen atomor a CH₂ group, with the proviso that when A is an oxygen atom, B is aCH₂ group, and when A is a CH₂ group, B is an oxygen atom; n is 1 or 2;m is 1, 2 or 3, with the proviso that the sum total of m+n is 2, 3 or 4;R¹⁰ is hydrogen, halogen, hydroxy, C₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,C₂₋₆alkenyl or C₂₋₆alkynyl; R¹¹ is hydrogen, halogen, hydroxy orC₁₋₄alkyl; or R¹⁰ and R¹¹ may together represent an oxo (═O) group, withthe proviso that the oxo group is not adjacent to the oxygen atomrepresented by either A or B; wherein one or both of R¹⁰ and R¹¹ mayreplace one or both hydrogen atoms in the CH₂ group represented by A orB; wherein when W is

R¹⁰ is hydrogen, C₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl,C₂₋₄alkyl substituted by a C₁₋₄alkoxy or hydroxyl group; R¹¹ is hydrogenor C₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, or C₁₋₄alkylsubstituted by C₁₋₄alkoxy, hydroxyl or phenyl, wherein said phenyl groupis optionally substituted by one, two or three substituents selectedfrom C₁₋₆alkyl, C₁₋₆alkoxy, halogen and trifluoromethyl; or R¹⁰, R¹¹ andthe nitrogen atom to which they are attached form a heteroaliphatic ringof 4 to 7 ring atoms, optionally substituted by one or two groupsselected from hydroxy, COR^(e), CO₂R^(e), C₁₋₄alkyl optionallysubstituted by a C₁₋₄alkoxy or hydroxyl group, or C₄alkoxy optionallysubstituted by a C₁₋₄alkoxy or hydroxyl group, which heteroaliphaticring may optionally contain an oxygen or sulphur ring atom, a group S(O)or S(O)₂ or a second nitrogen atom which will be part of a NH or NR^(d)moiety, where R^(d) is C₁₋₄alkyl optionally substituted by hydroxy orC₁₋₄alkoxy, and where R^(e) is hydrogen, C₁₋₄alkyl or benzyl; R¹²represents halogen, hydroxy, C₁₋₄alkoxy or fluoroC₁₋₄alkoxy, or where pis 2, then two R⁹ groups may together represent an oxo (═O) group; m iszero, 1 or 2; n is 1, 2 or 3, with the proviso that the sum total of m+nis 2 or 3; and p is zero, 1 or 2; wherein when W is

A represents NR¹² or S(O)_(q); B represents NR¹² or S(O)_(q), with theproviso that when A is S(O)_(q), then B is NR¹², and when A is NR¹²,then B is S(O)_(q); R¹⁰ and R¹¹ each independently represent hydrogen,fluorine, COR^(e), CO₂R^(e), C₁₋₄alkyl optionally substituted by aC₁₋₄alkoxy or hydroxyl group, or C₁₋₄alkoxy optionally substituted by aC₁₋₄alkoxy or hydroxyl group, where R^(e) is hydrogen, methyl ethyl orbenzyl; or, when they are attached to the same carbon atom, R¹⁰ and R¹¹may together represent ═O, ═CHCO₂R^(a), —O(CH₂)_(m)O—, —CH₂O(CH₂)_(p)—,—CH₂OCH₂C(O)—, —CH₂OCH₂CH(OH)—, —CH₂OCH₂C(CH₃)₂—, —CH₂OC(CH₃)₂CH₂—,—C(CH₃)₂OCH₂CH₂—, —CH₂C(O)OCH₂—, —OC(O)CH₂CH₂—, —C(O)OCH₂CH₂—,—C(O)OC(CH₃)₂CH₂—, —C(O)OCH₂C(CH₃)₂—, —OCH₂(CH₂)_(p)—, —OC(CH₃)₂CH₂CH₂—,—OCH₂C(CH₃)₂CH₂—, —OCH₂CH₂C(CH₃)₂—, —OCH₂CH═CHCH₂—, —OCH₂CH(OH)CH₂CH₂—,—OCH₂CH₂CH(OH)CH₂—, —OCH₂C(O)CH₂CH₂—, —OCH₂CH₂C(O)CH₂—, or a group ofthe formula

where R^(a) is as previously defined, or, where they are attached toadjacent carbon atoms, R¹⁰ and R¹¹ may together represent —OCH₂CH₂— or—OCH₂CH(OH)—, or R¹⁰ and R¹¹ may together form a fused benzene ring; or,R¹⁰ and R¹¹ together form a C₁₋₂alkylene bridge across the pyrrolidine,piperidine, morpholine or piperazine ring to which they are attached;R¹² represents hydrogen, benzyl, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, COC₁₋₆alkyl, CO₂C₁₋₆alkyl or C₂₋₄alkylsubstituted by a C₄alkoxy or hydroxyl group; R¹³ represents hydrogen,halogen, hydroxy, C₁₋₄alkyl, hydroxyC₁₋₄alkyl or fluoroC₁₋₄alkyl; m is 1or 2; p is 1, 2 or 3; and q is zero, 1 or 2; wherein when W is

R¹⁰ represents halogen, hydroxy, C₁₋₄alkoxy or fluoroC₁₋₄alkoxy, orwhere p is 2, then two R¹⁰ groups may together represent an oxo (═O)group; R¹¹ represents hydrogen, benzyl, C₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, or C₂₋₄alkyl substituted by a C₁₋₄alkoxy orhydroxyl group; m is zero, 1 or 2; n is zero or 1, with the proviso thatthe sum total of m+n is 1, 2 or 3, and with the further proviso thatwhen m is 2 then n is 1; and p is zero, 1 or 2; wherein when W is

X represents —CHF—, —CF₂—, —CH(OH)— or —CH(OC₁₋₄alkyl)-; Y represents—NR¹³R¹⁴ or a group selected from:

Z represents O, S, SO, SO₂ or NR¹²; R¹⁰ represents hydrogen, halogen,hydroxy, C₁₋₄alkoxy or fluoroC₁₋₄alkoxy; R¹¹ represents hydrogen,halogen, hydroxy, C₁₋₄alkoxy or fluoroC₁₋₄alkoxy; or R¹⁰ and R¹¹together represent an oxo (═O) group; R¹² represents C₁₋₆alkyl,COC₁₋₆alkyl, CO₂C₁₋₆alkyl; R¹³ and R¹⁴ each independently representhydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl or fluoroC₁₋₆alkyl, wherein saidalkyl or cycloalkyl groups are optionally substituted with a groupselected from hydroxy, C₁₋₄alkoxy, —NHCOC₁₋₄alkyl or —NHCO₂C₁₋₄alkyl; mis 1 or 2; n is 1 or 2; and p is 1 or 2; wherein when W is

X represents —CHR¹³—, —CF₂— or —C(═O)—; R¹⁰ represents halogen, hydroxy,C₁₋₄alkoxy or fluoroC₁₋₄alkoxy, or where p is 2, then two R¹⁰ groups maytogether represent an oxo (═O) group; R¹¹ represents hydrogen, benzyl,C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, COC₁alkyl,CO₂C₁₋₆alkyl or C₂₋₄alkyl substituted by a C₁₋₄alkoxy or hydroxyl group;R¹² represents hydrogen, fluorine, hydroxy, C₁₋₄alkoxy, or R¹² is linkedto R¹¹ such that there is formed a ring, the linkage —R¹²—R¹¹— beingselected from: (a) —OC(O)—, (b) —OS(O)₂—, (c) -ZCH₂CH₂—, (d)-ZCH₂CH₂CH₂—, (e) -ZCH₂C(O)—, (f) -ZCH₂CH₂C(O)—, (g) -ZC(O)CH₂—, (h)-ZC(O)CH₂CH₂—, and (i) -ZCH₂C(O)CH₂—; wherein Z represents O, NH orN(C₁₋₆alkyl); m is 1 or 2; and p is zero, 1 or 2; or a pharmaceuticallyacceptable salt thereof.
 16. A compound as claimed in claim 15 of theformula (Ia)

wherein A, B, R¹⁰, R¹¹, m and n are as hereinbefore defined as for whenW is

or a pharmaceutically acceptable salt thereof.
 17. A compound as claimedin claim 16 of the formula (Iaa)

wherein A¹ is fluorine or CF₃; A² is fluorine or CF₃; A³ is hydrogen orfluorine; A⁴ is hydrogen, fluorine or bromine; A⁵ is methyl orhydroxymethyl; and A, B, R¹⁰ and R¹¹ are as defined in claim 2; or apharmaceutically acceptable salt thereof.
 18. A compound as claimed inclaim 16 of the formula (Iab)

wherein X represents CHOH or C═O; R¹ is fluorine or trifluoromethyl; R²is fluorine or trifluoromethyl; R³ is methyl or hydroxymethyl; R⁴ ishydrogen or fluorine; and R⁵ is hydrogen or fluorine; or apharmaceutically acceptable salt thereof.
 19. A compound as claimed inclaim 18 of the formula (Iaba)

wherein A¹ is hydrogen or fluorine; and A² is hydrogen or fluorine; or apharmaceutically acceptable salt thereof.
 20. A compound as claimed inclaim 15 selected from:(4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;(4S)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;(4R)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;(4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane;8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran-4-yl)]methyl-1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane;8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl(tetrahydropyran-4-yl)]methyl-2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane;8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1-oxa-8-aza-spiro[4.5]decane;8-[(2R,3S,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane;8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decane;8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-2,2-dimethyl-1-oxa-8-aza-spiro[4.5]decane;8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1-oxa-8-aza-spiro[4.5]decane;8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyl-tetrahydropyran-4-yl]methyl-1,1-dimethyl-2-oxa-8-aza-spiro[4.5]decane;8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-one;(4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-4-methyl-8-aza-spiro[4.5]decan-4-ol;(4R)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3-bromo-4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-8-aza-spiro[4.5]decan-4-ol;(4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-2-oxa-4-ethynyl-8-aza-spiro[4.5]decan-4-ol;(8S)-2-[((2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-6-oxa-2-azaspiro[3.4]octan-8-ol;(8R)-2-[((2R,3R,4R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenyl)tetrahydro-2H-pyran-4-yl)methyl]-6-oxa-2-azaspiro[3.4]octan-8-ol;(4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-phenyltetrahydropyran-4-yl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol;(4RS)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-4-ol;(4R*)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol;(4S*)-8-[(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)tetrahydropyran-4-yl]methyl-1-oxa-8-azaspiro[4.5]decan-4-ol;(4R)-8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-4-methoxy-2-oxa-8-azaspiro[4.5]decane;(4R)-8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)tetrahydro-2H-pyran-4-yl)methyl]-4-methoxy-2-oxa-8-azaspiro[4.5]decane;8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-1-oxa-8-azaspiro[4.5]decan-3-ol;8-[((2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-phenyltetrahydro-2H-pyran-4-yl)methyl]-1-oxa-8-azaspiro[4.5]decan-3-one;(2R or S,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)tetrahydro-N-(phenylmethyl)-2-furanmethanamine;(2S or R,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)tetrahydro-N-(phenylmethyl)-2-furanmethanamine;(2R or S,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)tetrahydro-2-furanmethanamine;(2S or R,5R orS)-5-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-tetrahydro-3-phenyl-2H-pyran-4-yl)-N,N-diethyltetrahydro-2-furanmethanamine;(3R orS)-3-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)thiomorpholine;and (3S orR)-3-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)thiomorpholine;(2S)-2-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-methylazetidine;(2R)-2-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-methylazetidine;4-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)piperidin-4-ol;4-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-cyclopropylpiperidin-4-ol;and4-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-(1-methylethyl)piperidin-4-ol;(αR orS)-α-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-piperidineethanol;(αS orR)-α-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)-1-piperidineethanol;and (αR orS,2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-α-[(dimethylamino)methyl]-3-phenyl-2H-pyran-4-methanol;1,1-dimethylethyl(2R or S)-2-[(R orS)-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)hydroxymethyl]-1-pyrrolidinecarboxylate;(1R or S, 7aR orS)-1-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one;and (2R,3R,4R,αR or S)-α-[(2R orS)-2-pyrrolidinyl]-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-methanol;or a pharmaceutically acceptable salt thereof.
 21. A pharmaceuticalcomposition comprising a compound according to claim 15 together with atleast one pharmaceutically acceptable carrier or excipient.
 22. Apharmaceutical composition comprising a compound according to claim 20together with at least one pharmaceutically acceptable carrier orexcipient.
 23. A method for the treatment or prevention of physiologicaldisorders associated with an excess of tachykinins, which methodcomprises administration to a patient in need thereof of a tachykininreducing amount of a compound according to claim
 15. 24. A method forthe treatment or prevention of physiological disorders associated withan excess of tachykinins, which method comprises administration to apatient in need thereof of a tachykinin reducing amount of a compoundaccording to claim
 20. 25. A method for the treatment or prevention ofpain or inflammation, migraine, emesis, postherpetic neuralgia,depression or anxiety, which method comprises administration to apatient in need thereof of a therapeutically effective amount of acompound according to claim
 15. 26. A method for the treatment orprevention of pain or inflammation, migraine, emesis, postherpeticneuralgia, depression or anxiety, which method comprises administrationto a patient in need thereof of a therapeutically effective amount of acompound according to claim 20.